Crystallized glucocorticoid receptor ligand binding domain polypeptide and screening methods employing same

ABSTRACT

A method of modifying a test nuclear receptor (NR) polypeptide is disclosed. The method provides a test NR polypeptide sequence having a characteristic that is targeted for modification; aligning the test NR polypeptide sequence with at least one reference NR polypeptide sequence for which an X-ray structure is available; building a three-dimensional model for the test NR polypeptide using the three-dimensional coordinates of the X-ray structure(s) of at least one reference polypeptide and its sequence alignment with the test NR polypeptide sequence; examining the three-dimensional model of the test NR polypeptide sequence for characteristic differences with the reference polypeptide; and mutating at least one amino acid residue in the test NR polypeptide sequence at a characteristic difference, whereby the test NR polypeptide is modified.

CROSS REFERENCE TO RELATED APPLICATIONS

The present patent application is based on and claims priority to U.S. Provisional Application Ser. No. 60/305,902, entitled “CRYSTALLIZED GLUCOCORTICOID RECEPTOR LIGAND BINDING DOMAIN POLYPEPTIDE AND SCREENING METHODS EMPLOYING SAME”, which was filed Jul. 17, 2001 and is incorporated herein by reference in its entirety.

TECHNICAL FIELD

The present invention relates generally to a modified glucocortcoid receptor polypeptide, to a modified glucocortcoid receptor ligand binding domain polypeptide, to the structure of a glucocorticoid receptor ligand binding domain, and to the structure of a glucocorticoid receptor ligand binding domain in complex with a ligand and a co-activator. The invention further relates to methods by which a soluble glucocorticoid polypeptide can be generated and by which modulators and ligands of nuclear receptors, particularly steroid receptors and more particularly glucosteroid receptors and the ligand binding domains thereof can be identified. Abbreviations ATP adenosine triphosphate ADP adenosine diphosphate AR androgen receptor CAT chloramphenicol acyltransferase CBP CREB binding protein cDNA complementary DNA DBD DNA binding domain DMSO dimethyl sulfoxide DNA deoxyribonucleic acid DTT dithiothreitol EDTA ethylenediaminetetraacetic acid ER estrogen receptor GR glucocorticoid receptor GRE glucocorticoid responsive element GST glutathione S-transferase HEPES N-2-Hydroxyethylpiperazine-N'-2-ethanesulfonic acid HSP heat shock protein kDa kilodalton(s) LBD ligand binding domain MR mineralcorticoid receptor NDP nucleotide diphosphate NID nuclear receptor interaction domain NTP nucleotide triphosphate PAGE polyacrylamide gel electrophoresis PCR polymerase chain reaction pI isoelectric point PPAR peroxisome proliferator-activated receptor PR progesterone receptor RAR retinoid acid receptor RXR retinoid X receptor SDS sodium dodecyl sulfate SDS-PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis TIF2 transcription intermediary factor 2 TR thyroid receptor VDR vitamin D receptor

Amino Acid Abbreviations Single-Letter Three-Letter Code Code Name A Ala Alanine V Val Valine L Leu Leucine I Ile Isoleucine P Pro Proline F Phe Phenylalanine W Trp Tryptophan M Met Methionine G Gly Glycine S Ser Serine T Thr Threonine C Cys Cysteine Y Tyr Tyrosine N Asn Asparagine Q Gln Glutamine D Asp Aspartic Acid E Glu Glutamic Acid K Lys Lysine R Arg Arginine H His Histidine

Functionally Equivalent Codons Amino Acid Codons Alanine Ala A GCA GCC GCG GCU Cysteine Cys C UGC UGU Aspartic Acid Asp D GAC GAU Glumatic acid Glu E GAA GAG Phenylalanine Phe F UUC UUU Glycine Gly G GGA GGC GGG GGU Histidine His H CAC CAU Isoleucine Ile I AUA AUC AUU Lysine Lys K AAA AAG Methionine Met M AUG Asparagine Asn N AAC AAU Proline Pro P CCA CCC CCG CCU Glutamine Gln Q CAA CAG Threonine Thr T ACA ACC ACG ACU Valine Val V GUA GUC GUG GUU Tryptophan Trp W UGG Tyrosine Tyr Y UAC UAU Leucine Leu L UUA UUG CUA CUC CUG CUU Arginine Arg R AGA AGG CGA CGC CGG CGU Serine Ser S ACG AGU UCA UCC UCG UCU

BACKGROUND ART

Nuclear receptors reside in either the cytoplasm or nucleus of eukaryotic cells and represent a superfamily of proteins that specifically bind a physiologically relevant small molecule, such as a hormone or vitamin. As a result of a molecule binding to a nuclear receptor, the nuclear receptor changes the ability of a cell to transcribe DNA, i.e. nuclear receptors modulate the transcription of DNA. However, they can also have transcription independent actions.

Unlike integral membrane receptors and membrane-associated receptors, nuclear receptors reside in either the cytoplasm or nucleus of eukaryotic cells. Thus, nuclear receptors comprise a class of intracellular, soluble, ligand-regulated transcription factors. Nuclear receptors include but are not limited to receptors for androgens, mineralcorticoids, progestins, estrogens, thyroid hormones, vitamin D, retinoids, eicosanoids, peroxisome proliferators and, pertinently, glucocorticoids. Many nuclear receptors, identified by either sequence homology to known receptors (See, e.g., Drewes et al., (1996) Mol. Cell. Biol. 16:925-31) or based on their affinity for specific DNA binding sites in gene promoters (See, e.g., Sladek et al., Genes Dev. 4:2353-65), have unascertained ligands and are therefore commonly termed “orphan receptors”.

Glucocorticoids are an example of a cellular molecule that has been associated with cellular proliferation. Glucocorticoids are known to induce growth arrest in the G1-phase of the cell cycle in a variety of cells, both in vivo and in vitro, and have been shown to be useful in the treatment of certain cancers. The glucocorticoid receptor (GR) belongs to an important class of transcription factors that alter the expression of target genes in response to a specific hormone signal. Accumulated evidence indicates that receptor associated proteins play key roles in regulating glucocorticoid signaling. The list of cellular proteins that can bind and co-purify with the GR is constantly expanding.

Glucocorticoids are also used for their anti-inflammatory effect on the skin, joints, and tendons. They are important for treatment of disorders where inflammation is thought to be caused by immune system activity. Representative disorders of this sort include but are not limited to rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, and connective tissue diseases like systemic lupus erythmatosus. Glucocorticoids are also used to treat asthma and are widely used with other drugs to prevent the rejection of organ transplants. Some cancers of the blood (leukemias) and lymphatic system (lymphomas) can also respond to corticosteroid drugs.

Glucocorticoids exert several effects in tissues that express receptors for them. They regulate the expression of several genes either positively or negatively and in a direct or indirect manner. They are also known to arrest the growth of certain lymphoid cells and in some cases cause cell death (Harmon et al., (1979) J. Cell Physiol. 98: 267-278; Yamamoto, (1985) Ann. Rev. Genet. 19: 209-252; Evans, (1988) Science 240:889-895; Beato, (1989) Cell 56:335-344; Thompson, (1989) Cancer Res. 49: 2259s-2265s.). Due in part to their ability to kill cells, glucocorticoids have been used for decades in the treatment of leukemias, lymphomas, breast cancer, solid tumors and other diseases involving irregular cell growth, e.g. psoriasis. The inclusion of glucocorticoids in chemotherapeutic regimens has contributed to a high rate of cure of certain leukemias and lymphomas which were formerly lethal (Homo-Delarche, (1984) Cancer Res. 44: 431-437). Although it is clear that glucocorticoids exert these effects after binding to their receptors, the mechanism of cell kill is not completely understood, although several hypotheses have been proposed. Among the more prominent hypotheses are: the deinduction of critical lymphokines, oncogenes and growth factors; the induction of supposed “lysis genes”; alterations in calcium ion influx; the induction of endonucleases; and the induction of a cyclic AMP-dependent protein kinase (McConkey et al., (1989) Arch. Biochem. Biophys. 269: 365-370; Cohen & Duke, (1984) J. Immunol. 152: 38-42; Eastman-Reks & Vedeckis, (1986) Cancer Res. 46: 2457-2462; Kelso & Munck, (1984) J. Immunol. 133:784-791; Gruol et al., (1989) Molec. Endocrinol. 3: 2119-2127; Yuh & Thompson, (1989) J. Biol. Chem. 264: 10904-10910).

Polypeptides, including the glucocorticoid receptor ligand binding domain, have a three-dimensional structure determined by the primary amino acid sequence and the environment surrounding the polypeptide. This three-dimensional structure establishes the polypeptide's activity, stability, binding affinity, binding specificity, and other biochemical attributes. Thus, knowledge of a protein's three-dimensional structure can provide much guidance in designing agents that mimic, inhibit, or improve its biological activity.

The three-dimensional structure of a polypeptide can be determined in a number of ways. Many of the most precise methods employ X-ray crystallography (See, e.g., Van Holde, (1971) Physical Biochemistry, Prentice-Hall, New Jersey, pp. 221-39). This technique relies on the ability of crystalline lattices to diffract X-rays or other forms of radiation. Dffraction experiments suitable for determining the three-dimensional structure of macromolecules typically require high-quality crystals. Unfortunately, such crystals have been unavailable for the ligand binding domain of a human glucocorticoid receptor, as well as many other proteins of interest. Thus, high-quality diffracting crystals of the ligand binding domain of a human glucocorticoid receptor in complex with a ligand and a peptide would greatly assist in the elucidation of its three-dimensional structure.

Clearly, the solved crystal structure of the ligand binding domain of a glucocorticoid receptor polypeptide would be useful in the design of modulators of activity mediated by the glucocorticoid receptor. Evaluation of the available sequence data shows that GRα is particularly similar to MR, PR and AR. The GRα LBD has approximately 56%, 54% and 50% sequence identity to the MR, PR and AR LBDs, respectively. The GRβ amino acid sequence is identical to the GRα amino acid sequence for residues 1-727, but the remaining 15 residues in GRβ show no significant similarity to the remaining 50 residues in GRα. If no X-ray structure were available for GRα, then one could build a model for GRα using the available X-ray structures of PR and/or AR as templates. These theoretical models have some utility, but cannot be as accurate as a true X-ray structure, such as the X-ray structure disclosed here. Because of their limited accuracy, a model for GRα will generally be less useful than an X-ray structure for the design of agonists, antagonists and modulators of GRα.

The solved GRα-ligand-co-activator crystal structure would provide structural details and insights necessary to design a modulator of GRα that maximizes preferred requirements for any modulator, i.e. potency and specificity. By exploiting the structural details obtained from a GRα-ligand-co-activator crystal structure, it would be possible to design a GRα modulator that, despite GRα's similarity with other steroid receptors and nuclear receptors, exploits the unique structural features of the ligand binding domain of human GRα. A GRα modulator developed using structure-assisted design would take advantage of heretofore unknown GRα structural considerations and thus be more effective than a modulator developed using homology-based design. Potential or existent homology models cannot provide the necessary degree of specificity. A GRα modulator designed using the structural coordinates of a crystalline form of the ligand binding domain of GRα in complex with a ligand and a co-activator would also provide a starting point for the development of modulators of other nuclear receptors.

Although several journal articles have referred to GR mutants having “increased ligand efficacy” in cell-based assays, it has not been mentioned that such mutants could have improved solution properties so that they could provide a suitable reagent for purification, assay, and crystallization. See Garabedian & Yamamoto (1992) Mol. Biol. Cell 3: 1245-1257; Kralli, et al., (1995) Proc. Natl. Acad. Sci. 92: 4701-4705; Bohen (1995) J. Biol. Chem. 270: 29433-29438; Bohen (1998) Mol. Cell. Biol. 18: 3330-3339; Freeman et al., (2000) Genes Dev. 14: 422-434.

Indeed, it is well documented that GR associates with molecular chaperones (such as hsp90, hsc70, and p23). In the past, it has been considered that GR would either not be active or soluble if purified away from these binding partners. In fact, it has even been mentioned that GR must be in complex with hsp90 in order to adopt a high affinity steroid binding conformation. See Xu et al. (1998) J. Biol. Chem. 273: 13918-13924; Rajapandi et al. (2000) J. Biol. Chem. 275: 22597-22604.

Still other journal articles have reported E.coli expression of GST-GR, but also noted a failure to purify the purported polypeptide. See Ohara-Nemoto et al., (1990) J. Steroid Biochem. Molec. Biol. 37: 481-490; Caamano et al., (1994) Annal. NY Acad. Sci. 746: 68-77.

What is needed, therefore, is a purified, soluble GRα LBD polypeptide for use in structural studies, as well as methods for making the same. Such methods would also find application in the preparation of modified NRs in general.

What is also needed is a crystallized form of a GRα ligand binding domain, preferably in complex with a ligand and more preferably in complex with a ligand and a co-activator. Acquisition of crystals of the GRα ligand binding domain polypeptide permits the three-dimensional structure of a GRα ligand binding domain (LBD) polypeptide to be determined. Knowledge of the three dimensional structure can facilitate the design of modulators of GR-mediated activity. Such modulators can lead to therapeutic compounds to treat a wide range of conditions, including inflammation, tissue rejection, auto-immunity, malignancies such as leukemias and lymphomas, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of the TH1/TH2 cytokine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, Little's syndrome, inflammatory bowel disease, systemic lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arteritis, rheumatoid arthritis, osteoarthritis, hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis, cirrhosis, inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneous T-cell lymphoma. Other applications of a GR modulator developed in accordance with the present invention can be employed to treat Human Immunodeficiency Virus (HIV), cell apoptosis, and can be employed in treating cancerous conditions including, but not limited to, Kaposi's sarcoma, immune system activation and modulation, desensitization of inflammatory responses, IL-1 expression, natural killer cell development, lymphocytic leukemia, treatment of retinitis pigmentosa. Other applications for such a modulator comprise modulating cognitive performance, memory and learning enhancement, depression, addiction, mood disorders, chronic fatigue syndrome, schizophrenia, stroke, sleep disorders, anxiety, immunostimulants, repressors, wound healing and a role as a tissue repair agent or in anti-retroviral therapy.

SUMMARY OF THE INVENTION

A method of modifying a test NR polypeptide is disclosed. The method can comprise: providing a test NR polypeptide sequence having a characteristic that is targeted for modification; aligning the test NR polypeptide sequence with at least one reference NR polypeptide sequence for which an X-ray structure is available, wherein the at least one reference NR polypeptide sequence has a characteristic that is desired for the test NR polypeptide; building a three-dimensional model for the test NR polypeptide using the three-dimensional coordinates of the X-ray structure(s) of the at least one reference polypeptide and its sequence alignment with the test NR polypeptide sequence; examining the three-dimensional model of the test NR polypeptide for differences with the at least one reference polypeptide that are associated with the desired characteristic; and mutating at least one amino acid residue in the test NR polypeptide sequence located at a difference identified above to a residue associated with the desired characteristic, whereby the test NR polypeptide is modified.

A method of altering the solubility of a test NR polypeptide is also disclosed in accordance with the present invention. In a preferred embodiment, the method comprises: (a) providing a reference NR polypeptide sequence and a test NR polypeptide sequence; (b) comparing the reference NR polypeptide sequence and the test NR polypeptide sequence to identify one or more residues in the test NR sequence that are more or less hydrophilic than a corresponding residue in the reference NR polypeptide sequence; and (c) mutating the residue in the test NR polypeptide sequence identified in step (b) to a residue having a different hydrophilicity, whereby the solubility of the test NR polypeptide is altered. Optionally, the reference NR polypeptide sequence is an AR or a PR sequence, and the test polypeptide sequence is a GR polypeptide sequence. Alternatively, the reference polypeptide sequence is a crystalline GR LBD. The comparing of step (b) is preferably by sequence alignment.

An isolated GR polypeptide comprising a mutation in a ligand binding domain, wherein the mutation alters the solubility of the ligand binding domain, is also disclosed. An isolated GR polypeptide, or functional portion thereof, having one or more mutations comprising a substitution of a hydrophobic amino acid residue by a hydrophilic amino acid residue in a ligand binding domain is also disclosed. Preferably, in each case, the mutation can be at a residue selected from the group consisting of V552, W557, F602, L636, Y648, W712, L741, L535, V538, C638, M691, V702, Y648, Y660, L685, M691, V702, W712, L733, Y764 and combinations thereof. More preferably, the mutation is selected from the group consisting of V552K, W557S, F602S, F602D, F602E, L636E, Y648Q, W712S, L741R, L535T, V538S, C638S, M691T, V702T, W712T and combinations thereof. Antibodies against such polypeptides are also disclosed, as are methods of detecting such polypeptides and methods of identifying substances that modulate the biological activity of such polypeptides.

An isolated nucleic acid molecule encoding a GR polypeptide comprising a mutation in a ligand binding domain, wherein the mutation alters the solubility of the ligand binding domain, or encoding a GR LBD polypeptide, or functional portion thereof, having one or more mutations comprising a substitution of a hydrophobic amino acid residue by a hydrophilic amino acid residue, is also disclosed. A chimeric gene, comprising the nucleic acid molecule operably linked to a heterologous promoter, a vector comprising the chimeric gene, and a host cell comprising the chimeric gene are also disclosed. Methods for detecting such a nucleic acid molecule are also disclosed.

A substantially pure GRα ligand binding domain polypeptide in crystalline form is disclosed. Preferably, the crystalline form has lattice constants of a=b=126.014 A, c=86.312 Å, α=900, β=900, γ=120°. Preferably, the crystalline form is a hexagonal crystalline form. More preferably, the crystalline form has a space group of P6₁. Even more preferably, the GRα ligand binding domain polypeptide has the F602S amino acid sequence shown in Example 2. Even more preferably, the GRα ligand binding domain has a crystalline structure further characterized by the coordinates corresponding to Table 4.

Preferably, the GRα ligand binding domain polypeptide is in complex with a ligand. Optionally, the crystalline form contains two GRα ligand binding domain polypeptides in the asymmetric unit. Preferably, the crystalline form is such that the three-dimensional structure of the crystallized GRα ligand binding domain polypeptide can be determined to a resolution of about 2.8 Å or better. Even more preferably, the crystalline form contains one or more atoms having a molecular weight of 40 grams/mol or greater.

A method for determining the three-dimensional structure of a crystallized GR ligand binding domain polypeptide to a resolution of about 2.8 Å or better, the method comprising: (a) crystallizing a GR ligand binding domain polypeptide; and (b) analyzing the GR ligand binding domain polypeptide to determine the three-dimensional structure of the crystallized GR ligand binding domain polypeptide, whereby the three-dimensional structure of a crystallized GR ligand binding domain polypeptide is determined to a resolution of about 2.8 Å or better. Preferably, the analyzing is by X-ray diffraction. More preferably, the crystallization is accomplished by the hanging drop method, and wherein the GRα ligand binding domain is mixed with a reservoir.

A method of generating a crystallized GR ligand binding domain polypeptide, the method comprising: (a) incubating a solution comprising a GR ligand binding domain with a reservoir; and (b) crystallizing the GR ligand binding domain polypeptide using the hanging drop method, whereby a crystallized GR ligand binding domain polypeptide is generated.

A method of designing a modulator of a nuclear receptor, the method comprising: (a) designing a potential modulator of a nuclear receptor that will make interactions with amino acids in the ligand binding site of the nuclear receptor based upon the atomic structure coordinates of a GR ligand binding domain polypeptide; (b) synthesizing the modulator; and (c) determining whether the potential modulator modulates the activity of the nuclear receptor, whereby a modulator of a nuclear receptor is designed.

A method of designing a modulator that selectively modulates the activity of a GRα polypeptide the method comprising: (a) obtaining a crystalline form of a GRα ligand binding domain polypeptide; (b) determining the three-dimensional structure of the crystalline form of the GRα ligand binding domain polypeptide; and (c) synthesizing a modulator based on the three-dimensional structure of the crystalline form of the GRα ligand binding domain polypeptide, whereby a modulator that selectively modulates the activity of a GRα polypeptide is designed. Preferably, the method further comprises contacting a GRα ligand binding domain polypeptide with the potential modulator; and assaying the GRα ligand binding domain polypeptide for binding of the potential modulator, for a change in activity of the GRα ligand binding domain polypeptide, or both. More preferably, the crystalline form is in orthorhombic form. Even more preferably, the crystals are such that the three-dimensional structure of the crystallized GRα ligand binding domain polypeptide can be determined to a resolution of about 2.8 Å or better.

A method of screening a plurality of compounds for a modulator of a GR ligand binding domain polypeptide, the method comprising: (a) providing a library of test samples; (b) contacting a GR ligand binding domain polypeptide with each test sample; (c) detecting an interaction between a test sample and the GR ligand binding domain polypeptide; (d) identifying a test sample that interacts with the GR ligand binding domain polypeptide; and (e) isolating a test sample that interacts with the GR ligand binding domain polypeptide, whereby a plurality of compounds is screened for a modulator of a GR ligand binding domain polypeptide. Preferably, the test samples are bound to a substrate, and more preferably, the test samples are synthesized directly on a substrate. The GR ligand binding domain polypeptide can be in soluble or crystalline form.

A method for identifying a GR modulator is also disclosed. In a preferred embodiment, the method comprises: (a) providing atomic coordinates of a GR ligand binding domain to a computerized modeling system; and (b) modeling ligands that fit spatially into the binding pocket of the GR ligand binding domain to thereby identify a GR modulator, whereby a GR modulator is identified. Preferably, the method further comprises identifying in an assay for GR-mediated activity a modeled ligand that increases or decreases the activity of the GR.

A method of identifying modulator that selectively modulates the activity of a GRα polypeptide compared to other GR polypeptides, the method comprising: (a) providing atomic coordinates of a GRα ligand binding domain to a computerized modeling system; and (b) modeling a ligand that fits into the binding pocket of a GRα ligand binding domain and that interacts with conformationally constrained residues of a GRα conserved among GR subtypes, whereby a modulator that selectively modulates the activity of a GRα polypeptide compared to other polypeptides is identified. Preferably, the method further comprises identifying in a biological assay for GRα activity a modeled ligand that selectively binds to GRα and increases or decreases the activity of said GRα.

A method of designing a modulator of a GR polypeptide, the method comprising: (a) selecting a candidate GR ligand; (b) determining which amino acid or amino acids of a GR polypeptide interact with the ligand using a three-dimensional model of a crystallized protein comprising a GRα LBD; (c) identifying in a biological assay for GR activity a degree to which the ligand modulates the activity of the GR polypeptide; (d) selecting a chemical modification of the ligand wherein the interaction between the amino acids of the GR polypeptide and the ligand is predicted to be modulated by the chemical modification; (e) synthesizing a chemical compound with the selected chemical modification to form a modified ligand; (f) contacting the modified ligand with the GR polypeptide; (g) identifying in a biological assay for GR activity a degree to which the modified ligand modulates the biological activity of the GR polypeptide; and (h) comparing the biological activity of the GR polypeptide in the presence of modified ligand with the biological activity of the GR polypeptide in the presence of the unmodified ligand, whereby a modulator of a GR polypeptide is designed. Preferably, the GR polypeptide is a GRα polypeptide. More preferably, the three-dimensional model of a crystallized protein is a GRα LBD polypeptide with a bound ligand. Optionally, the method further comprises repeating steps (a) through (f) if the biological activity of the GR polypeptide in the presence of the modified ligand varies from the biological activity of the GR polypeptide in the presence of the unmodified ligand.

An assay method for identifying a compound that inhibits binding of a ligand to a GR polypeptide, the assay method comprising: (a) designing a test inhibitor compound based on the three dimensional atomic coordinates of GR; (b) incubating a GR polypeptide with a ligand in the presence of a test inhibitor compound; (c) determining an amount of ligand that is bound to the GR polypeptide, wherein decreased binding of ligand to the GR protein in the presence of the test inhibitor compound relative to binding of ligand in the absence of the test inhibitor compound is indicative of inhibition; and (d) identifying the test compound as an inhibitor of ligand binding if decreased ligand binding is observed, whereby a compound that inhibits binding of a ligand to a GR polypeptide is identified.

A method of identifying a NR modulator that selectively modulates the biological activity of one NR compared to GRα is also disclosed. The method comprises: (a) providing an atomic structure coordinate set describing a GRα ligand binding domain structure and at least one other atomic structure coordinate set describing a NR ligand binding domain, each ligand binding domain comprising a ligand binding site; (b) comparing the atomic structure coordinate sets to identify at least one diference between the sets; (c) designing a candidate ligand predicted to interact with the difference of step (b); (d) synthesizing the candidate ligand; and (e) testing the synthesized candidate ligand for an ability to selectively modulate a NR as compared to GRα, whereby a NR modulator that selectively modulates the biological activity NR compared to GRα is identified.

Accordingly, it is an object of the present invention to provide a three dimensional structure of the ligand binding domain of a GR. The object is achieved in whole or in part by the present invention.

An object of the invention having been stated hereinabove, other objects will be evident as the description proceeds, when taken in connection with the accompanying Drawings and Laboratory Examples as best described hereinbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts E. coli expression of mutant 6xHisGST-GR(521-777) F602S (SEQ ID NO:12) via SDS-PAGE. Staining was accomplished using the commercially available PROBLUE product.

FIG. 1B depicts E coli expression of mutant 6xHisGST-GR(521-777) F602D (SEQ ID NO:14) via SDS-PAGE. Staining was accomplished using the commercially available PROBLUE product.

FIG. 1C depicts purification of E. coli expressed GR(521-777)F602S (SEQ ID NO:12) via SDS-PAGE. Staining was accomplished using the commercially available PROBLUE product.

FIG. 1D shows the partial purification of E. Coli expressed GR (521-777) for several mutants isolated by the Lacl Fusion system.

FIGS. 2A-2C depict characterization of GR binding to dexamethasone and the TIF2 LXXLL (SEQ ID NO:18) motif.

FIG. 2A is a graph depicting the binding of 10 nM fluorescein dexamethasone to varied concentrations of GST-GR LBD (F602S) 521-777 (circles), GR LBD (F602S) 521-777 (triangles) and GR LBD (F602S) 521-777 in the presence of 100 uM unlabeled dexamethasone (squares) as measured by fluorescence polarization.

FIG. 2B is a graph depicting ligand-dependent binding of TIF2 LXXLL(SEQ ID NO:18) motif to GR LBD. The binding of varied concentrations of GST-GR LBD (F602S) 521-777 to immobilized TIF2 732-756 peptide (SEQ ID NO:17) in the presence of a five-fold excess of dexamethasone (triangles), RU486 (squares) and no compound (circles) was measured by surface plasmon resonance. Each point is the average of two determinations.

FIG. 2C is a graph depicting that TIF2 coactivator peptide enhances stability of GR dexamethasone binding activity. The effect of 25 uM coactivator peptide TIF2 732-756 (diamonds) or no peptide (squares) on the binding of GST-GR LBD (F602S) 521-777 to 10 nM fluorescein dexamethasone with time is determined by fluorescence polarization.

FIG. 3A is a worm/ribbon diagram depicting the overall arrangement of the GR LBD diamers. Two GR LBDs are shown in white and gray worm representation. TIF2 peptides are shown in gray ribbon and the two dexamethasone ligands are shown in space filling.

FIG. 3B is a worm/ribbon diagram depicting one orientation of the GR/TIF2/Dex complex. TIF peptide is shown in ribbon and GR is shown in worm. The AF2 helix of the GR is shown in gray worm. The key structural elements are marked and are described herein below.

FIG. 3C is a worm/ribbon diagram depicting a second orientation of the GR/TIF2/DEX complex. TIF2 peptide is shown in ribbon and GR is shown in worm. The AF2 helix of GR is shown in gray worm. The key structural elements are marked and are described herein below.

FIGS. 4A and 4B depict the overlap of the GR LBD with the AR LBD (FIG. 4A) and the PR LBD (FIG. 4B). The GR is in thick line. AR and PR are in the thin line. Only the backbone C alpha atoms are shown.

FIG. 5 is a sequence alignment of steroid receptors, particularly an alignment of the F602S GRα sequence (SEQ ID NO:31) with MR(SEQ ID NO:26), PR(SEQ ID NO:27), AR(SEQ ID NO:28), ERα(SEQ ID NO:29), and ERβ(SEQ ID NO:30). Residues that lie within 5.0 angstroms of the ligand are identified with small square boxes around the one-letter amino acid code. The ligands used for this calculation are dexamethasone (for GR), progesterone (for PR), dihydrotestosterone (for AR), estradiol (for ERα) and genistein (for ERβ). The alpha-helices and beta-strands observed in the X-ray structures are identified by the larger boxes and captions. Note that the secondary structure of MR is not publicly known at this time, and thus is not annotated in the Figure. More than one structure is available for PR, AR, ERα and ERβ, and, in some cases, the alpha-helices have different endpoints in these different X-ray structures. The variation in the alpha-helices is indicated here by using boxes with thicker and thinner linewidths, where the thicker linewidth box encompasses residues that adopt the same secondary structure in all available X-ray structures, and thinner linewidth boxes encompass residues that adopt an alpha-helical structure in some but not all X-ray structures. The secondary structures were determined by graphical examination of the X-ray structures.

FIG. 6A depicts the GR ligand binding pocket. The GR LBD is shown in a worm representation and the pocket is shown with a white surface.

FIG. 6B is a diagram that depicts surfaces at the GR-dexamethasone interface. The electron density is calculated with Fo coefficiency and shown at a one sigma cutoff. Key residues surrounding the ligand are also labeled, as described herein below.

FIG. 7 is a diagram of molecular interactions between GR and dexamethasone. Both Van der Waals contacts and hydrogen bonds are indicated with dotted lines.

FIG. 8 is a wire frame diagram showing the structure around the F602 mutation in the GRα LBD polypeptide. The lipophilic F602 side-chain of the wild-type GRα protein would be located in a hydrophilic environment and could destabilize the protein. Changing the phenylalanine (F) to a serine (S) allows the S602 side-chain and NH group to make direct hydrogen bonds with two water molecules (1H20 and 2H20). Other residues involved with the two water molecules are also shown and are described herein below.

BRIEF DESCRIPTION OF SEQUENCES IN THE SEQUENCE LISTING

SEQ ID NOs:1 and 2 are, respectively, a DNA sequence encoding a wild type full-length human glucocorticoid receptor (GenBank Accession No. 31679) and the amino acid sequence (GenBank Accession No. 121069) of a human glucocorticoid receptor encoded by the DNA sequence.

SEQ ID NOs:3 and 4 are, respectively, a DNA sequence encoding a F602S full-length human glucocorticoid receptor and the amino acid sequence of a human glucocorticoid receptor encoded by the DNA sequence.

SEQ ID NOs:5 and 6 are, respectively, a DNA sequence encoding a F602D full-length human glucocorticoid receptor and the amino acid sequence of a human glucocorticoid receptor encoded by the DNA sequence.

SEQ ID NOs:7 and 8 are, respectively, a DNA sequence encoding a preferred embodiment of a full-length human glucocorticoid receptor of the present invention and the amino acid sequence of a human glucocorticoid receptor encoded by the DNA sequence. These sequences thus include variable amino acids at the following locations: V552, W557, F602, L636, Y648, W712, L741, L535, V538, C638, M691, V702, Y648, Y660, L685, M691, V702, W712, L733, and Y764, thus reflecting the mutagenesis approach of the present invention disclosed herein below. Thus, a full length human glucocorticoid receptor of the present invention can include a mutation at any one of these residues, and/or at any combination of these residues.

SEQ ID NOs:9 and 10 are, respectively, a DNA sequence encoding a wild type ligand binding domain of a human glucocorticoid receptor and the amino acid sequence of a human glucocorticoid receptor encoded by the DNA sequence.

SEQ ID NOs:11 and 12 are, respectively, a DNA sequence encoding a ligand binding domain (residues 521-777) of a human glucocorticoid receptor containing a phenylalanine to serine mutation at residue 602 and the amino acid sequence of a human glucocorticoid receptor encoded by the DNA sequence.

SEQ ID NOs:13 and 14 are, respectively, a DNA sequence encoding a ligand binding domain (residues 521-777) of a human glucocorticoid receptor containing a phenylalanine to aspartic acid mutation at residue 602 and the amino acid sequence of a human glucocorticoid receptor encoded by the DNA sequence.

SEQ ID NOs:15 and 16 are, respectively, a DNA sequence encoding a preferred embodiment of a ligand binding domain of a human glucocorticoid receptor of the present invention and the amino acid sequence of a human glucocorticoid receptor encoded by the DNA sequence. These sequences thus include variable amino acids at the following locations: V552, W557, F602, L636, Y648, W712, L741, L535, V538, C638, M691, V702, Y648, Y660, L685, M691, V702, W712, L733, and Y764, thus reflecting the mutagenesis approach of the present invention disclosed herein below. Thus, a ligand binding domain of a human glucocorticoid receptor of the present invention can include a mutation at any one of these residues, and/or at any combination of these residues.

SEQ ID NO:17 is an amino acid sequence of amino acid residues 732-756 of the human TIF2 protein.

SEQ ID NO:18 is an LXXLL motif of the human TIF2 protein.

SEQ ID NOs:19-20 are oligonucleotide primers used to engineer a polyhistidine tag in frame to the sequence encoding glutathione S-transferase (GST).

SEQ ID NO:21 is the resulting amino acid sequence of the modified GST.

SEQ ID NOs:22-25 are oligonucleotide primers used in the mutagenesis approach of the present invention.

SEQ ID NOs:26-31 are the ligand binding domain pplypeptides of MR(SEQ ID NO:26), PR(SEQ ID NO:27), AR(SEQ ID NO:28), ERα(SEQ ID NO:29), ERβ(SEQ ID NO:30), and F602S GRα(SEQ ID NO:31) respectively. All of these sequences are also shown in FIG. 5. Note that the GRα sequence shown of SEQ ID NO:31 starts at residue 527, whereas the F602S sequence of SEQ ID NO:12 starts at residue 521.

SEQ ID NO:32 is an amino acid sequence of a ligand binding domain (residues 521-777) of a human glucocorticoid receptor containing a phenylalanine to serine mutation at residue 602, wherein the first two residues comprise a thrombin cleavage site encoded by vector.

SEQ ID NO: 33 is an amino acid sequence of a ligand binding domain (residues 521-777) of a human glucocorticoid receptor comprising a W557R mutation.

SEQ ID NO: 34 is an amino acid sequence of a ligand binding domain (residues 521-777) of a human glucocorticoid receptor comprising a Q615L mutation.

SEQ ID NO: 35 is an amino acid sequence of a ligand binding domain (residues 521-777) of a human glucocorticoid receptor comprising a Q615H mutation.

SEQ ID NO: 36 is an amino acid sequence of a ligand binding domain (residues 521-777) of a human glucocorticoid receptor comprising a A574T mutation.

SEQ ID NO: 37 is an amino acid sequence of a ligand binding domain (residues 521-777) of a human glucocorticoid receptor comprising a L620M mutation.

SEQ ID NO: 38 is an amino acid sequence of a ligand binding domain (residues 521-777) of a human glucocorticoid receptor comprising the double mutation F602L/A580T.

SEQ ID NO: 39 is an amino acid sequence of a ligand binding domain (residues 521-777) of a human glucocorticoid receptor comprising the double mutation L563F/G583C.

SEQ ID NO: 40 is an amino acid sequence of a ligand binding domain (residues 521-777) of a human glucocorticoid receptor comprising the double mutation L664H/M752T.

SEQ ID NO: 41 is an amino acid sequence of a ligand binding domain (residues 521-777) of a human glucocorticoid receptor comprising the double mutation L563F/T744N.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for the generation of NR, SR and GR polypeptides and NR, SR or GR mutants (preferably GRα and GRα LBD mutants), and the ability to solve the crystal structures of those that crystallize. Indeed, a GRα LBD having a point mutation was crystallized and solved in one aspect of the present invention. Thus, an aspect of the present invention involves the use of both targeted and random mutagenesis of the GR gene for the production of a recombinant protein with improved solution characteristics for the purpose of crystallization, characterization of biologically relevant protein-protein interactions, and compound screening assays. The present invention, relating to GR LBD F602S and other LBD mutations, shows that GR can be overexpressed using an E. coli expression system and that active GR protein can be purified, assayed, and crystallized.

Until disclosure of the present invention presented herein, the ability to obtain crystalline forms of the ligand binding domain of GRα has not been realized. And until disclosure of the present invention presented herein, a detailed three-dimensional crystal structure of a GRα LBD polypeptide has not been solved.

In addition to providing structural information, crystalline polypeptides provide other advantages. For example, the crystallization process itself further purifies the polypeptide, and satisfies one of the classical criteria for homogeneity. In fact, crystallization frequently provides unparalleled purification quality, removing impurities that are not removed by other purification methods such as HPLC, dialysis, conventional column chromatography, and other methods. Moreover, crystalline polypeptides are sometimes stable at ambient temperatures and free of protease contamination and other degradation associated with solution storage. Crystalline polypeptides can also be useful as pharmaceutical preparations. Finally, crystallization techniques in general are largely free of problems such as denaturation associated with other stabilization methods (e.g., lyophilization). Once crystallization has been accomplished, crystallographic data provides useful structural information that can assist the design of compounds that can serve as modulators (e.g. agonists or antagonists), as described herein below. In addition, the crystal structure provides information useful to map a receptor binding domain, which can then be mimicked by a chemical entity that can serve as an antagonist or agonist.

I. Definitions

Following long-standing patent law convention, the terms “a” and “an” mean “one or more” when used in this application, including the claims.

As used herein, the term “agonist” means an agent that supplements or potentiates the bioactivity of a functional GR gene or protein or of a polypeptide encoded by a gene that is up- or down-regulated by a GR polypeptide and/or a polypeptide encoded by a gene that contains a GR binding site or response element in its promoter region. By way of specific example, an “agonist’ is a compound that interacts with the steroid hormone receptor to promote a transcriptional response. An agonist can induce changes in a receptor that places the receptor in an active conformation that allows them to influence transcription, either positively or negatively. There can be several different ligand-induced changes in the receptors conformation. The term “agonist” specifically encompasses partial agonists.

As used herein, the terms “α-helix”, “alphα-helix” and “alpha helix” are used interchangeably and mean the conformation of a polypeptide chain wherein the polypeptide backbone is wound around the long axis of the molecule in a left-handed or right-handed direction, and the R groups of the amino acids protrude outward from the helical backbone, wherein the repeating unit of the structure is a single turnoff the helix, which extends about 0.56 nm along the long axis.

As used herein, the term “antagonist” means an agent that decreases or inhibits the bioactivity of a functional GR gene or protein, or that supplements or potentiates the bioactivity of a naturally occurring or engineered non-functional GR gene or protein. Alternatively, an antagonist can decrease or inhibit the bioactivity of a functional gene or polypeptide encoded by a gene that is up- or down-regulated by a GR polypeptide and/or contains a GR binding site or response element in its promoter region. An antagonist can also supplement or potentiate the bioactivity of a naturally occurring or engineered non-functional gene or polypeptide encoded by a gene that is up- or down-regulated by a GR polypeptide, and/or contains a GR binding site or response element in its promoter region. By way of specific example, an “antagonist” is a compound that interacts with the steroid hormone receptor to inhibit a transcriptional response. An antagonist can bind to a receptor but fail to induce conformational changes that alter the receptor's transcriptional regulatory properties or physiologically relevant conformations. Binding of an antagonist can also block the binding and therefore the actions of an agonist. The term “antagonist” specifically encompasses partial antagonists.

As used herein, the terms “β-sheet”, “beta-sheet” and “beta sheet” are used interchangeably and mean the conformation of a polypeptide chain stretched into an extended zig-zig conformation. Portions of polypeptide chains that run “parallel” all run in the same direction. Polypeptide chains that are “antiparallel” run in the opposite direction from the parallel chains.

As used herein, the terms “binding pocket of the GR ligand binding domain”, “GR ligand binding pocket” and “GR binding pocket” are used interchangeably, and refer to the large cavity within the GR ligand binding domain where a ligand can bind. This cavity can be empty, or can contain water molecules or other molecules from the solvent, or can contain ligand atoms. The main binding pocket is the region of space encompassed the residues depicted FIG. 7. The binding pocket also includes regions of space near the “main” binding pocket that not occupied by atoms of GR but that are near the “main” binding pocket, and that are contiguous with the “main” binding pocket.

As used herein, the term “biological activity” means any observable effect flowing from interaction between a GR polypeptide and a ligand. Representative, but non-limiting, examples of biological activity in the context of the present invention include transcription regulation, ligand binding and peptide binding.

As used herein, the terms “candidate substance” and “candidate compound” are used interchangeably and refer to a substance that is believed to interact with another moiety, for example a given ligand that is believed to interact with a complete, or a fragment of, a GR polypeptide, and which can be subsequently evaluated for such an interaction. Representative candidate substances or compounds include xenobiotics such as drugs and other therapeutic agents, carcinogens and environmental pollutants, natural products and extracts, as well as endobiotics such as glucocorticosteroids, steroids, fatty acids and prostaglandins. Other examples of candidate compounds that can be investigated using the methods of the present invention include, but are not restricted to, agonists and antagonists of a GR polypeptide, toxins and venoms, viral epitopes, hormones (e.g., glucocorticosteroids, opioid peptides, steroids, etc.), hormone receptors, peptides, enzymes, enzyme substrates, co-factors, lectins, sugars, oligonucleotides or nucleic acids, oligosaccharides, proteins, small molecules and monoclonal antibodies.

As used herein, the terms “cells,” “host cells” or “recombinant host cells” are used interchangeably and mean not only to the particular subject cell, but also to the progeny or potential progeny of such a cell. Because certain modifications can occur in succeeding generations due to either mutation or environmental influences, such progeny might not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.

As used herein, the terms “chimeric protein” or “fusion protein” are used interchangeably and mean a fusion of a first amino acid sequence encoding a GR polypeptide with a second amino acid sequence defining a polypeptide domain foreign to, and not homologous with, any domain of a GR polypeptide. A chimeric protein can include a foreign domain that is found in an organism that also expresses the first protein, or it can be an “interspecies” or “intergenic” fusion of protein structures expressed by different kinds of organisms. In general, a fusion protein can be represented by the general formula X-GR-Y, wherein GR represents a portion of the protein which is derived from a GR polypeptide, and X and Y are independently absent or represent amino acid sequences which are not related to a GR sequence in an organism, which includes naturally occurring mutants.

As used herein, the term “co-activator” means an entity that has the ability to enhance transcription when it is bound to at least one other entity. The association of a co-activator with an entity has the ultimate effect of enhancing the transciption of one or more sequences of DNA. In the context of the present invention, transcription is preferably nuclear receptor-mediated. By way of specific example, in the present invention TIF2 (the human analog of mouse glucocorticoid receptor interaction protein 1 (GRIP1)) can bind to a site on the glucorticoid receptor, an event that can enhance transcription. TIF2 is therefore a co-activator of the glucocorticoid receptor. Other GR co-activators can include SRC1.

As used herein, the term “co-repressor” means an entity that has the ability to repress transcription when it is bound to at least one other entity. In the context of the present invention, transcription is preferably nuclear receptor-mediated. The association of a co-repressor with an entity has the ultimate effect of repressing the transciption of one or more sequences of DNA.

As used herein, the term “crystal laftice” means the array of points defined by the vertices of packed unit cells.

As used herein, the term “detecting” means confirming the presence of a target entity by observing the occurrence of a detectable signal, such as a radiologic or spectroscopic signal that will appear exclusively in the presence of the target entity.

As used herein, the term “DNA segment” means a DNA molecule that has been isolated free of total genomic DNA of a particular species. In a preferred embodiment, a DNA segment encoding a GR polypeptide refers to a DNA segment that comprises any of the odd numbered SEQ ID NOs:1-16, but can optionally comprise fewer or additional nucleic acids, yet is isolated away from, or purified free from, total genomic DNA of a source species, such as Homo sapiens. Included within the term “DNA segment” are DNA segments and smaller fragments of such segments, and also recombinant vectors, including, for example, plasmids, cosmids, phages, viruses, and the like.

As used herein, the term “DNA sequence encoding a GR polypeptide” can refer to one or more coding sequences within a particular individual. Moreover, certain differences in nucleotide sequences can exist between individual organisms, which are called alleles. It is possible that such allelic differences might or might not result in differences in amino acid sequence of the encoded polypeptide yet still encode a protein with the same biological activity. As is well known, genes for a particular polypeptide can exist in single or multiple copies within the genome of an individual. Such duplicate genes can be identical or can have certain modifications, including nucleotide substitutions, additions or deletions, all of which still code for polypeptides having substantially the same activity.

As used herein, the phrase “enhancer-promoter” means a composite unit that contains both enhancer and promoter elements. An enhancer-promoter is operatively linked to a coding sequence that encodes at least one gene product.

As used herein, the term “expression” generally refers to the cellular processes by which a biologically active polypeptide is produced.

As used herein, the term “gene” is used for simplicity to refer to a functional protein, polypeptide or peptide encoding unit. As will be understood by those in the art, this functional term includes both genomic sequences and cDNA sequences. Preferred embodiments of genomic and cDNA sequences are disclosed herein.

As used herein, the term “glucocorticoid” means a steroid hormone glucocorticoid. “Glucocorticoids” are agonists for the glucocorticoid receptor. Compounds which mimic glucocorticoids are also be defined as glucocorticoid receptor agonists. A preferred glucocorticoid receptor agonist is dexamethasone. Other common glucocorticoid receptor agonists include cortisol, cortisone, prednisolone, prednisone, methylprednisolone, trimcinolone, hydrocortisone, and corticosterone. As used herein, glucocorticoid is intended to include, for example, the following generic and brand name corticosteroids: cortisone (CORTONE ACETATE, ADRESON, ALTESONA, CORTELAN, CORTISTAB, CORTISYL, CORTOGEN, CORTONE, SCHEROSON); dexamethasone-oral (DECADRON-ORAL, DEXAMETH, DEXONE, HEXADROL-ORAL, DEXAMETHASONE INTENSOL, DEXONE 0.5, DEXONE 0.75, DEXONE 1.5, DEXONE 4); hydrocortisone-oral (CORTEF, HYDROCORTONE); hydrocortisone cypionate (CORTEF ORAL SUSPENSION); methylprednisolone-oral (MEDROL-ORAL); prednisolone-oral (PRELONE, DELTA-CORTEF, PEDIAPRED, ADNISOLONE, CORTALONE, DELTACORTRIL, DELTASOLONE, DELTASTAB, DI-ADRESON F, ENCORTOLONE, HYDROCORTANCYL, MEDISOLONE, METICORTELONE, OPREDSONE, PANAAFCORTELONE, PRECORTISYL, PRENISOLONA, SCHERISOLONA, SCHERISOLONE); prednisone (DELTASONE, LIQUID PRED, METICORTEN, ORASONE 1, ORASONE 5, ORASONE 10, ORASONE 20, ORASONE 50, PREDNICEN-M, PREDNISONE INTENSOL, STERAPRED, STERAPRED DS, ADASONE, CARTANCYL, COLISONE, CORDROL, CORTAN, DACORTIN, DECORTIN, DECORTISYL, DELCORTIN, DELLACORT, DELTADOME, DELTACORTENE, DELTISONA, DIADRESON, ECONOSONE, ENCORTON, FERNISONE, NISONA, NOVOPREDNISONE, PANAFCORT, PANASOL, PARACORT, PARMENISON, PEHACORT, PREDELTIN, PREDNICORT, PREDNICOT, PREDNIDIB, PREDNIMENT, RECTODELT, ULTRACORTEN, WINPRED); triamcinolone-oral (KENACORT, ARISTOCORT, ATOLONE, SHOLOG A, TRAMACORT-D, TRI-MED, TRIAMCOT, TRISTO-PLEX, TRYLONE D, U-TRI-LONE).

As used herein, the term “glucocorticoid receptor,” abbreviated herein as “GR,” means the receptor for a steroid hormone glucocorticoid. A glucocorticoid receptor is a steroid receptor and, consequently, a nuclear receptor, since steroid receptors are a subfamily of the superfamily of nuclear receptors. The term “GR” means any polypeptide sequence that can be aligned with human GR such that at least 70%, preferably at least 75%, of the amino acids are identical to the corresponding amino acid in the human GR. The term “GR” also encompasses nucleic acid sequences where the corresponding translated protein sequence can be considered to be a GR. The term “GR” includes invertebrate homologs, whether now known or hereafter identified; preferably, GR nucleic acids and polypeptides are isolated from eukaryotic sources. “GR” further includes vertebrate homologs of GR family members, including, but not limited to, mammalian and avian homologs. Representative mammalian homologs of GR family members include, but are not limited to, murine and human homologs. “GR” specifically encompasses all GR isoforms, including GRα and GRβ. GRβ is a splicing variant with 100% identity to GRα, except at the C-terminus, where 50 residues in GRα have been replaced with 15 residues in GRβ.

As used herein, the terms “GR gene product, UGR protein”, “GR polypeptide”, and “GR peptide” are used interchangeably and mean peptides having amino acid sequences which are substantially identical to native amino acid sequences from the organism of interest and which are biologically active in that they comprise all or a part of the amino acid sequence of a GR polypeptide, or cross-react with antibodies raised against a GR polypeptide, or retain all or some of the biological activity (e.g., DNA or ligand binding ability and/or transcriptional regulation) of the native amino acid sequence or protein. Such biological activity can include immunogenicity. Representative embodiments are set forth in any even numbered SEQ ID NOs:2-16. The terms “GR gene product”, “GR protein”, “GR polypeptide”, and “GR peptide” also include analogs of a GR polypeptide. By “analog” is intended that a DNA or peptide sequence can contain alterations relative to the sequences disclosed herein, yet retain all or some of the biological activity of those sequences. Analogs can be derived from genomic nucleotide sequences as are disclosed herein or from other organisms, or can be created synthetically. Those skilled in the art will appreciate that other analogs, as yet undisclosed or undiscovered, can be used to design and/or construct GR analogs. There is no need for a “GR gene product”, “GR protein”, “GR polypeptide”, or “GR peptide” to comprise all or substantially all of the amino acid sequence of a GR polypeptide gene product. Shorter or longer sequences are anticipated to be of use in the invention; shorter sequences are herein referred to as “segments”. Thus, the terms “GR gene product”, “GR protein”, “GR polypeptide”, and “GR peptide” also include fusion or recombinant GR polypeptides and proteins comprising sequences of the present invention. Methods of preparing such proteins are disclosed herein and are known in the art.

As used herein, the terms “GR gene” and “recombinant GR gene” mean a nucleic acid molecule comprising an open reading frame encoding a GR polypeptide of the present invention, including both exon and (optionally) intron sequences.

As used herein, hexagonal unit cell” means a unit cell wherein a=b≠c; and α=β=90, γ=120°. The vectors a, b and c describe the unit cell edges and the angles α, β, and γ describe the unit cell angles. In a preferred embodiment of the present invention, the unit cell has lattice constants of a=b=126.014 Å, c=86.312 Å, α=90°, β=90°, γ=120°. While preferred lattice constants are provided, a crystalline polypeptide of the present invention also comprises variations from the preferred lattice constants, wherein the varations range from about one to about two percent. Thus, for example, a crystalline polypeptide of the present invention can also comprise lattice constants of about 125 or about 127.

As used herein, the term “hybridization” means the binding of a probe molecule, a molecule to which a detectable moiety has been bound, to a target sample.

As used herein, the term “interact” means detectable interactions between molecules, such as can be detected using, for example, a yeast two hybrid assay. The term “interact” is also meant to include “binding” interactions between molecules. Interactions can, for example, be protein-protein or protein-nucleic acid in nature.

As used herein, the term “intron” means a DNA sequence present in a given gene that is not translated into protein.

As used herein, the term “isolated” means oligonucleotides substantially free of other nucleic acids, proteins, lipids, carbohydrates or other materials with which they can be associated, such association being either in cellular material or in a synthesis medium. The term can also be applied to polypeptides, in which case the polypeptide will be substantially free of nucleic acids, carbohydrates, lipids and other undesired polypeptides.

As used herein, the term “labeled” means the attachment of a moiety, capable of detection by spectroscopic, radiologic or other methods, to a probe molecule.

As used herein, the term “modified” means an alteration from an entity's normally occurring state. An entity can be modified by removing discrete chemical units or by adding discrete chemical units. The term “modified” encompasses detectable labels as well as those entities added as aids in purification.

As used herein, the term “modulate” means an increase, decrease, or other alteration of any or all chemical and biological activities or properties of a wild-type or mutant GR polypeptide, preferably a wild-type or mutant GR polypeptide. The term “modulation” as used herein refers to both upregulation (i.e., activation or stimulation) and downregulation (i.e. inhibition or suppression) of a response,, and includes responses that are upregulated in one cell type or tissue, and down-regulated in another cell type or tissue.

As used herein, the term “molecular replacement” means a method that involves generating a preliminary model of the wild-type GR ligand binding domain, or a GR mutant crystal whose structure coordinates are unknown, by orienting and positioning a molecule or model whose structure coordinates are known (e.g., a nuclear receptor) within the unit cell of the unknown crystal so as best to account for the observed diffraction pattern of the unknown crystal. Phases can then be calculated from this model and combined with the observed amplitudes to give an approximate Fourier synthesis of the structure whose coordinates are unknown. This, in turn, can be subject to any of the several forms of refinement to provide a final, accurate structure of the unknown crystal. See, e.g., Laftman, (1985) Method Enzymol., 115: 55-77; Rossmann, ed, (1972) The Molecular Replacement Method, Gordon & Breach, New York. Using the structure coordinates of the ligand binding domain of GR provided by this invention, molecular replacement can be used to determine the structure coordinates of a crystalline mutant or homologue of the GR ligand binding domain, or of a different crystal form of the GR ligand binding domain.

As used herein, the term “mutation” carries its traditional connotation and means a change, inherited, naturally occurring or introduced, in a nucleic acid or polypeptide sequence, and is used in its sense as generally known to those of skill in the art.

As used herein, the term “nuclear receptor”, occasionally abbreviated herein as “NR”, means a member of the superfamily of receptors that comprises at least the subfamilies of steroid receptors, thryroid hormone receptors, retinoic acid receptors and vitamin D receptors. Thus, a given nuclear receptor can be further classified as a member of a subfamily while retaining its status as a nuclear receptor.

As used herein, the phrase “operatively linked” means that an enhancer-promoter is connected to a coding sequence in such a way that the transcription of that coding sequence is controlled and regulated by that enhancer-promoter. Techniques for operatively linking an enhancer-promoter to a coding sequence are well known in the art; the precise orientation and location relative to a coding sequence of interest is dependent, inter alia, upon the specific nature of the enhancer-promoter.

As used herein, the term “partial agonist” means an entity that can bind to a receptor and induce only part of the changes in the receptors that are induced by agonists. The differences can be qualitative or quantitative. Thus, a partial agonist can induce some of the conformation changes induced by agonists, but not others, or it can only induce certain changes to a limited extent.

As used herein, the term “partial antagonist” means an entity that can bind to a receptor and inhibit only part of the changes in the receptors that are induced by antagonists. The differences can be qualitative or quantitative. Thus, a partial antagonist can inhibit some of the conformation changes induced by an antagonist, but not others, or it can inhibit certain changes to a limited extent.

As used herein, the term “polypeptide” means any polymer comprising any of the 20 protein amino acids, regardless of its size. Although “protein” is often used in reference to relatively large polypeptides, and “peptide” is often used in reference to small polypeptides, usage of these terms in the art overlaps and varies. The term “polypeptide” as used herein refers to peptides, polypeptides and proteins, unless otherwise noted. As used herein, the terms “protein”, “polypeptide” and “peptide” are used interchangeably herein when referring to a gene product.

As used herein, the term “primer” means a sequence comprising two or more deoxyribonucleotides or ribonucleotides, preferably more than three, and more preferably more than eight and most preferably at least about 20 nucleotides of an exonic or intronic region. Such oligonucleotides are preferably between ten and thirty bases in length.

As used herein, the term “sequencing” means the determining the ordered linear sequence of nucleic acids or amino acids of a DNA or protein target sample, using conventional manual or automated laboratory techniques.

As used herein, the term “space group” means the arrangement of symmetry elements of a crystal.

As used herein, the term “steroid receptor” means a nuclear receptor that can bind or associate with a steroid compound. Steroid receptors are a subfamily of the superfamily of nuclear receptors. The subfamily of steroid receptors comprises glucocorticoid receptors and, therefore, a glucocorticoid receptor is a member of the subfamily of steroid receptors and the superfamily of nuclear receptors.

As used herein, the terms “structure coordinates” and “structural coordinates” mean mathematical coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of X-rays by the atoms (scattering centers) of a molecule in crystal form. The diffraction data are used to calculate an electron density map of the repeating unit of the crystal. The electron density maps are used to establish the positions of the individual atoms within the unit cell of the crystal.

Those of skill in the art understand that a set of coordinates determined by X-ray crystallography is not without standard error. In general, the error in the coordinates tends to be reduced as the resolution is increased, since more experimental diffraction data is available for the model fitting and refinement. Thus, for example, more diffraction data can be collected from a crystal that diffracts to a resolution of 2.8 angstroms than from a crystal that diffracts to a lower resolution, such as 3.5 angstroms. Consequently, the refined structural coordinates will usually be more accurate when fitted and refined using data from a crystal that diffracts to higher resolution. The design of ligands and modulators for GR or any other NR depends on the accuracy of the structural coordinates. If the coordinates are not sufficiently accurate, then the design process will be ineffective. In most cases, it is very difficult or impossible to collect sufficient diffraction data to define atomic coordinates precisely when the crystals diffract to a resolution of only 3.5 angstroms or poorer. Thus, in most cases, it is difficult to use X-ray structures in structure-based ligand design when the X-ray structures are based on crystals that diffract to a resolution of only 3.5 angstroms or poorer. However, common experience has shown that crystals diffracting to 2.8 angstroms or better can yield X-ray structures with sufficient accuracy to greatly facilitate structure-based drug design. Further improvement in the resolution can further facilitate structure-based design, but the coordinates obtained at 2.8 angstroms resolution are generally adequate for most purposes.

Also, those of skill in the art will understand that NR proteins can adopt different conformations when different ligands are bound. In particular, NR proteins will adopt substantially different conformations when agonists and antagonists are bound. Subtle variations in the conformation can also occur when different agonists are bound, and when different antagonists are bound. These variations can be difficult or impossible to predict from a single X-ray structure. Generally, structure-based design of GR modulators depends to some degree on a knowledge of the differences in conformation that occur when agonists and antagonists are bound. Thus, structure-based modulator design is most facilitated by the availability of X-ray structures of complexes with potent agonists as well as potent antagonists.

As used herein, the term “substantially pure” means that the polynucleotide or polypeptide is substantially free of the sequences and molecules with which it is associated in its natural state, and those molecules used in the isolation procedure. The term “substantially free” means that the sample is at least 50%, preferably at least 70%, more preferably 80% and most preferably 90% free of the materials and compounds with which is it associated in nature.

As used herein, the term “target cell” refers to a cell, into which it is desired to insert a nucleic acid sequence or polypeptide, or to otherwise effect a modification from conditions known to be standard in the unmodified cell. A nucleic acid sequence introduced into a target cell can be of variable length. Additionally, a nucleic acid sequence can enter a target cell as a component of a plasmid or other vector or as a naked sequence.

As used herein, the term “transcription” means a cellular process involving the interaction of an RNA polymerase with a gene that directs the expression as RNA of the structural information present in the coding sequences of the gene. The process includes, but is not limited to the following steps: (a) the transcription initiation, (b) transcript elongation, (c) transcript splicing, (d) transcript capping, (e) transcript termination, (f) transcript polyadenylation, (g) nuclear export of the transcript, (h) transcript editing, and (i) stabilizing the transcript.

As used herein, the term “transcription factor” means a cytoplasmic or nuclear protein which binds to such gene, or binds to an RNA transcript of such gene, or binds to another protein which binds to such gene or such RNA transcript or another protein which in turn binds to such gene or such RNA transcript, so as to thereby modulate expression of the gene. Such modulation can additionally be achieved by other mechanisms; the essence of “transcription factor for a gene” is that the level of transcription of the gene is altered in some way.

As used herein, the term “unit cell” means a basic parallelipiped shaped block. The entire volume of a crystal can be constructed by regular assembly of such blocks. Each unit cell comprises a complete representation of the unit of pattern, the repetition of which builds up the crystal. Thus, the term “unit cell” means the fundamental portion of a crystal structure that is repeated infinitely by translation in three dimensions. A unit cell is characterized by three vectors a, b, and c, not located in one plane, which form the edges of a parallelepiped. Angles α, β, and γ define the angles between the vectors: angle α is the angle between vectors b and c; angle β is the angle between vectors a and c; and angle γ is the angle between vectors a and b. The entire volume of a crystal can be constructed by regular assembly of unit cells; each unit cell comprises a complete representation of the unit of pattern, the repetition of which builds up the crystal.

II. Description of Tables

Table 1 is chart of sequence identity between the ligand binding domains of several nuclear receptors.

Table 2 is a table listing mutations of the GR LBD (521-777) gene for testing solution solubility and stability. SEQ ID NOs:7-8 and 15-16 also comprise these mutations. Candidate mutated residues include but are not limited to Cys, Asn, Tyr, Lys, Ser, Asp, Glu, Gln, Arg or Thr.

Table 2A is a table listing mutations that were discovered using the Lacl-based “peptides-on-plasmids” technique with GR LBD.

Table 3 is a table summarizing the crystal and data statistics obtained from the crystallized ligand binding domain of GRα LBD that was co-crystallized with dexamethasone and a fragment of the co-activator TIF2. Data on the unit cell are presented, including data on the crystal space group, unit cell dimensions, molecules per asymmetric cell and crystal resolution.

Table 4 is a table of the atomic structure coordinate data obtained from X-ray diffraction from the ligand binding domain of GR (residues 521-777) in complex with desamethasone and a fragment of the co-activator TIF2.

Table 5 is a table of the atomic structure coordinates used as the initial model to solve the structure of the GR/TIF2/dexamethasone complex by molecular replacement. The GR model is a homology model built on the published structure of the progesterone receptor LBD and the SRC1 coactivator peptide from the PPARα/Compound 1/SRC1 structure.

III. General Considerations

The present invention will usually be applicable mutatis mutandis to nuclear receptors in general, more particularly to steroid receptors and even more particularly to glucocorticoid receptors, including GR isoforms, as discussed herein, based, in part, on the patterns of nuclear receptor and steroid receptor structure and modulation that have emerged as a consequence of the present disclosure, which in part discloses determining the three dimensional structure of the ligand binding domain of GRα in complex with dexamethasone and a fragment of the co-activator TIF2.

The nuclear receptor superfamily has been subdivided into two subfamilies: the GR subfamily (also referred to as the steroid receptors and denoted SRs), comprising GR, AR (androgen receptor), MR (mineralcorticoid receptor) and PR (progesterone receptor) and the thyroid hormone receptor (TR) subfamily, comprising TR, vitamin D receptor (VDR), retinoic acid receptor (RAR), retinoid X receptor (RXR), and most orphan receptors. This division has been made on the basis of DNA binding domain structures, interactions with heat shock proteins (HSP), and ability to form dimers.

Steroid receptors (SRs) form a subset of the superfamily of nuclear receptors. The glucocorticoid receptor is a steroid receptor and thus a member of the superfamily of nuclear receptors and the subset of steroid receptors. The human glucocorticoid receptor exists in two isoforms, GRα which consists of 777 amino acids and GRβ which consists of 742 amino acids. As noted, the alpha isoform of human glucocorticoid receptor is made up of 777 amino acids and is predominantly cytoplasmic in its unactivated, non-DNA binding form. When activated, it translocates to the nucleus. In order to understand the role played by the glucocorticoid receptor in the different cell processes, the receptor was mapped by transfecting receptor-negative and glucocorticoid-resistant cells with different steroid receptor constructs and reporter genes like chloramphenicol acyltransferase (CAT) or luciferase which had been covalently linked to a glucocorticoid responsive element (GRE). From these and other studies, four major functional domains have become evident.

From amino to carboxyl terminal end, these functional domains include the tau 1, DNA binding, and ligand binding domains in succession. The tau 1 domain spans amino acid positions 77-262 and regulates gene activation. The DNA binding domain is from amino acid positions 421-486 and has nine cysteine residues, eight of which are organized in the form of two zinc fingers analogous to Xenopus transcription factor IIIA. The DNA binding domain binds to the regulatory sequences of genes that are induced or deinduced by glucocorticoids. Amino acids 521 to 777 form the ligand binding domain, which binds glucocorticoid to activate the receptor. This region of the receptor also has the nuclear localization signal. Deletion of this carboxyl terminal end results in a receptor that is constitutively active for gene induction (up to 30% of wild type activity) and even more active for cell kill (up to 150% of wild type activity) (Giguere et al., (1986) Cell 46: 645-652; Hollenberg et al., (1987) Cell 49: 3946; Hollenberg & Evans, (1988) Cell 55: 899-906; Hollenberg et al., (1989) Cancer Res. 49: 2292s-2294s; Oro et al., (1988) Cell 55: 1109-1114; Evans, (1989) in Recent Progress in Hormone Research (Clark, ed.) Vol. 45, pp. 1-27, Academic Press, San Diego, Calif.; Green & Chambon, (1987) Nature 325: 75-78; Picard & Yamamoto, (1987) EMBO J. 6: 3333-3340; Picard et al., (1990) Cell Regul. 1: 291-299; Godowski et al., (1987) Nature 325: 365-368; Miesfeld et al., (1987) Science 236:423-427; Danielsen et al., (1989) Cancer Res. 49: 2286s-2291s; Danielsen et al., (1987) Molec. Endocrinol. 1: 816-822; Umesono & Evans, (1989) Cell 57: 1139-1146.). Despite the aforementioned indirect characterization of the structure of GRα, until the present disclosure, a detailed three-dimensional model of the ligand binding domain of GRα has not been achieved.

GR subgroup members are tightly bound by heat shock protein(s) (HSP) in the absence of ligand, dimerize following ligand binding and dissociation of HSP, and show homology in the DNA half sites to which they bind. These half sites also tend to be arranged as palindromes. TR subgroup members tend to be bound to DNA or other chromatin molecules when unliganded, can bind to DNA as monomers and dimers, but tend to form heterodimers, and bind DNA elements with a variety of orientations and spacings of the half sites, and also show homology with respect to the nucleotide sequences of the half sites. ER does not belong to either subfamily, since it resembles the GR subfamily in hsp interactions, and the TR subfamily in nuclear localization and DNA-binding properties.

Most members of the superfamily, including orphan receptors, possess at least two transcription activation subdomains, one of which is constitutive and resides in the amino terminal domain (AF-1), and the other of which (AF-2) resides in the ligand binding domain, whose activity is regulated by binding of an agonist ligand. The function of AF-2 requires an activation domain (also called transactivation domain) that is highly conserved among the receptor superfamily. Most LBDs contain an activation domain. Some mutations in this domain abolish AF-2 function, but leave ligand binding and other functions unaffected. Ligand binding allows the activation domain to serve as an interaction site for essential co-activator proteins that function to stimulate (or in some cases, inhibit) transcription. . Analysis and alignment of amino acid sequences, and X-ray and NMR structure determinations, have shown that nuclear receptors have a modular architecture with three main domains:

1) a variable amino-terminal domain;

2) a highly conserved DNA-binding domain (DBD); and

3) a less conserved carboxy-terminal ligand binding domain (LBD).

In addition, nuclear receptors can have linker segments of variable length between these major domains. Sequence analysis and X-ray crystallography, including the disclosure of the present invention, have confirmed that GR also has the same general modular architecture, with the same three domains. The function of GR in human cells presumably requires all three domains in a single amino acid sequence. However, the modularity of GR permits different domains of each protein to separately accomplish certain functions. Some of the functions of a domain within the full-length receptor are preserved when that particular domain is isolated from the remainder of the protein. Using conventional protein chemistry techniques, a modular domain can sometimes be separated from the parent protein. Using conventional molecular biology techniques, each domain can usually be separately expressed with its original function intact or, as discussed herein below, chimeras comprising two different proteins can be constructed, wherein the chimeras retain the properties of the individual functional domains of the respective nuclear receptors from which the chimeras were generated.

The carboxy-terminal activation subdomain, is in close three dimensional proximity in the LBD to the ligand, so as to allow for ligands bound to the LBD to coordinate (or interact) with amino acid(s) in the activation subdomain. As described herein, the LBD of a nuclear receptor can be expressed, crystallized, its three dimensional structure determined with a ligand bound (either using crystal data from the same receptor or a different receptor or a combination thereof), and computational methods used to design ligands to its LBD, particularly ligands that contain an extension moiety that coordinates the activation domain of the nuclear receptor.

The LBD is the second most highly conserved domain in these receptors. As its name suggests, the LBD binds ligands. With many nuclear receptors, including GR, binding of the ligand can induce a conformational change in the LBD that can, in turn, activate transcription of certain target genes. Whereas integrity of several different LBD sub-domains is important for ligand binding, truncated molecules containing only the LBD retain normal ligand-binding activity. This domain also participates in other functions, including dimerization, nuclear translocation and transcriptional activation, as described herein.

Nuclear receptors usually have HSP binding domains that present a region for binding to the LBD and can be modulated by the binding of a ligand to the LBD. For many of the nuclear receptors ligand binding induces a dissociation of heat shock proteins such that the receptors can form dimers in most cases, after which the receptors bind to DNA and regulate transcription. Consequently, a ligand that stabilizes the binding or contact of the heat shock protein binding domain with the LBD can be designed using the computational methods described herein.

With the receptors that are associated with the HSP in the absence of the ligand, dissociation of the HSP results in dimerization of the receptors. Dimerization is due to receptor domains in both the DBD and the LBD. Although the main stimulus for dimerization is dissociation of the HSP, the ligand-induced conformational changes in the receptors can have an additional facilitative influence. With the receptors that are not associated with HSP in the absence of the ligand, particularly with the TR, ligand binding can affect the pattern of dimerization. The influence depends on the DNA binding site context, and can also depend on the promoter context with respect to other proteins that can interact with the receptors. A common pattern is to discourage monomer formation, with a resulting preference for heterodimer formation over dimer formation on DNA.

Nuclear receptor LBDs usually have dimerization domains that present a region for binding to another nuclear receptor and can be modulated by the binding of a ligand to the LBD. Consequently, a ligand that disrupts the binding or contact of the dimerization domain can be designed using the computational methods described herein to produce a partial agonist or antagonist.

The amino terminal domain of GR is the least conserved of the three domains. This domain is involved in transcriptional activation and, its uniqueness might dictate selective receptor-DNA binding and activation of target genes by GR subtypes. This domain can display synergistic and antagonistic interactions with the domains of the LBD.

The DNA binding domain has the most highly conserved amino acid sequence amongst the GRs. It typically comprises about 70 amino acids that fold into two zinc finger motifs, wherein a zinc atom coordinates four cysteines. The DBD comprises two perpendicularly oriented α-helixes that extend from the base of the first and second zinc fingers. The two zinc fingers function in concert along with non-zinc finger residues to direct the GR to specific target sites on DNA and to align receptor dimer interfaces. Various amino acids in the DBD influence spacing between two half-sites (which usually comprises six nucleotides) for receptor dimerization. The optimal spacings facilitate cooperative interactions between DBDs, and D box residues are part of the dimerization interface. Other regions of the DBD facilitate DNA-protein and protein-protein interactions are involved in dimerization.

In nuclear receptors that bind to a HSP, the ligand-induced dissociation of HSP with consequent dimer formation allows, and therefore, promotes DNA binding. With receptors that are not associated (as in the absence of ligand), ligand binding tends to stimulate DNA binding of heterodimers and dimers, and to discourage monomer binding to DNA. However, with DNA containing only a single half site, the ligand tends to stimulate the receptor's binding to DNA. The effects are modest and depend on the nature of the DNA site and probably on the presence of other proteins that can interact with the receptors. Nuclear receptors usually have DBD (DNA binding domains) that present a region for binding to DNA and this binding can be modulated by the binding of a ligand to the LBD.

The modularity of the members of the nuclear receptor superfamily permits different domains of each protein to separately accomplish different functions, although the domains can influence each other. The separate function of a domain is usually preserved when a particular domain is isolated from the remainder of the protein. Using conventional protein chemistry techniques a modular domain can sometimes be separated from the parent protein. By employing conventional molecular biology techniques each domain can usually be separately expressed with its original function intact or chimerics of two different nuclear receptors can be constructed, wherein the chimerics retain the properties of the individual functional domains of the respective nuclear receptors from which the chimerics were generated.

Various structures have indicated that most nuclear receptor LBDs adopt the same general folding pattern. This fold consists of 10-12 alpha helices arranged in a bundle, together with several beta-strands, and linking segments. A preferred GRα LBD structure of the present invention has 10-11 helices, depending on whether helix-3′ is counted. Structural studies have shown that most of the alpha-helices and beta-strands have the same general position and orientation in all nuclear receptor structures, whether ligand is bound or not. However, the AF2 helix has been found in different positions and orientations relative to the main bundle, depending on the presence or absence of the ligand, and also on the chemical nature of the ligand. These structural studies have suggested that many nuclear receptors share a common mechanism of activation, where binding of activating ligands helps to stabilize the AF2 helix in a position and orientation adjacent to helices-3, -4, and -10, covering an opening to the ligand binding site. This position and orientation of the AF2 helix, which will be called the “active conformation”, creates a binding site for co-activators: See, e.g., Nolte et al., (1998) Nature 395:137-43; Shiau et al., (1998) Cell 95: 927-37. This co-activator binding site has a central lipophilic pocket that can accommodate leucine side-chains from co-activators, as well as a “charge-clamp” structure consisting essentially of a lysine residue from helix-3 and a glutamic acid residue from the AF2 helix.

Structural studies have shown that co-activator peptides containing the sequence LXXLL (where L is leucine and X can be a different amino acid in different cases) can bind to this co-activator binding site by making interactions with the charge clamp lysine and glutamic acid residues, as well as the central lipophilic region. This co-activator binding site is disrupted when the AF2 helix is shifted into other positions and orientations. In PPARγ, activating ligands such as rosiglitazone (BRL49653) make a hydrogen bonding interaction with tyrosine-473 in the AF2 helix. Nolte et al., (1998) Nature 395:137-43; Gampe et al., (2000) Mol. Cell 5: 545-55. Similarly, in GR, the dexamethasone ligand makes van der Waals interaction with the side chain of leucine-753 from the AF2 helix. This interaction is believed in part to stabilize the AF2 helix in the active conformation, thereby allowing co-activators to bind and thus activating transcription from target genes.

With certain antagonist ligands, or in the absence of any ligand, the AF2 helix can be held less tightly in the active conformation, or can be free to adopt other conformations. This would either destabilize or disrupt the co-activator binding site, thereby reducing or eliminating co-activator binding and transcription from certain target genes. Some of the functions of the GR protein depend on having the full-length amino acid sequence and certain partner molecules, such as co-activators and DNA. However, other functions, including ligand binding and ligand-dependent conformational changes, can be observed experimentally using isolated domains, chimeras and mutant molecules.

As described herein, the LBD of a GR can be mutated or engineered, expressed, crystallized, its three dimensional structure determined with a ligand bound as disclosed in the present invention, and computational methods can be used to design ligands to nuclear receptors, preferably to steroid receptors, and more preferably to glucocorticoid receptors.

IV. The Dexamethasone Ligand

Ligand binding can induce transcriptional activation functions in a variety of ways. One way is through the dissociation of the HSP from receptors. This dissociation, with consequent dimerization of the receptors and their binding to DNA or other proteins in the nuclear chromatin, allows transcriptional regulatory properties of the receptors to be manifest. This can be especially true of such functions on the amino terminus of the receptors.

Another way is to alter the receptor to interact with other proteins involved in transcription. These could be proteins that interact directly or indirectly with elements of the proximal promoter or proteins of the proximal promoter. Alternatively, the interactions can be through other transcription factors that themselves interact directly or indirectly with proteins of the proximal promoter. Several different proteins have been described that bind to the receptors in a ligand-dependent manner. In addition, it is possible that in some cases, the ligand-induced conformational changes do not affect the binding of other proteins to the receptor, but do affect their abilities to regulate transcription.

In one aspect of the present invention, a GR LBD was co-crystallized with a fragment of the co-activator TIF2 and the ligand dexamethasone. Dexamethasone is a synthetic adrenocortical steroid with a molecular weight of 392.47. The IUPAC name for dexamethasone is (11β, 16α)-9-fluoro-11β,17,21-trihydroxy-16α-methylpregna-1 4-diene-3,20-dione. The empirical formula for dexamethasone is C₂₂H₂₉FO₅. Dexamethasone is represented by the chemical structure:

Dexamethasone-based therapeutics are commercially available in a variety of forms and formulations. Dexamethasone can also be purchased from various suppliers such as Sigma (St. Louis Mo.), as well as starting materials for the synthesis of dexamethasone. The synthesis of dexamethasone, and dexamethasone derivatives, is known and described in a variety of sources, including Arth et al., (1958) J. Am. Chem. Soc. 80: 3161; Oliveto et al., (1958) J. Am. Chem. Soc. 4431, Fried & Sabo, (1954) J. Am Chem. Soc. 76: 1455; Hirschman et al., (1956) J. Am. Chem. Soc. 78: 4957 and U.S. Pat. No. 3,007,923 to Muller et al., all of which are incorporated herein in their entirety.

V. The TIF2 Fragment

The nuclear receptor co-activator TIF2 (SEQ ID NO:17) was co-crystallized in one aspect of the present invention. Structurally, the nuclear receptor coactivator TIF2 comprises one domain that reacts with a nuclear receptor (nuclear receptor interaction domain, abbreviated “NID”) and two autonomous activation domains, AD1 and AD2 (Voegel et al., (1998) EMBO J. 17: 507-519). The TIF2 NID comprises three NR-interacting modules, with each module comprising the motif, LXXLL (SEQ ID NO:18) (Voegel et al., (1998) EMBO J. 17: 507-519). Mutation of the motif abrogates TIF2's ability to interact with the ligand-induced activation function-2 (AF-2) found in the ligand-binding domains (LBDs) of many NRs. Presently, it is thought that TIF2 AD1 activity is mediated by CREB binding protein (CBP), however, TIF2 AD2 activity does not appear to involve interaction with CBP (Voegel et al., (1998) EMBO J. 17: 507-519).

In the present invention, residues 732-756 of the TIF2 protein (SEQ ID NO:17) were co-crystallized with GR and dexamethasone. These residues comprise the LXXLL (SEQ ID NO:18) of AD-2, the third motif in the linear sequence of TIF2. The TIF2 fragment is 25 residues in length and was synthesized using an automated peptide synthesis apparatus. SEQ ID NO:17, and other sequences corresponding to TIF2 and other co-activators and co-repressors, can be similarly synthesized using automated apparatuses.

VI. Production of NR, SR and GR Polypeptides

In a preferred embodiment, the present invention provides for the first time for the expression of a soluble GR polypeptide in bacteria, more preferably, in E. coli. The GR polypeptides of the present invention, disclosed herein, can thus now provide a variety of host-expression vector systems to express an NR, SR or GR coding sequence. These include but are not limited to microorganisms such as bacteria transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing an NR, SR or GR coding sequence; yeast transformed with recombinant yeast expression vectors containing an NR, SR or GR coding sequence; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing an NR, SR or GR coding sequence; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing an NR, SR or GR coding sequence; or animal cell systems. The expression elements of these systems vary in their strength and specificities. Methods for constructing expression vectors that comprise a partial or the entire native or mutated NR and GR polypeptide coding sequence and appropriate transcriptional/translational control signals include in vitro recombinant DNA techniques, synthetic techniques and in vivo recombination/genetic recombination. See, for example, the techniques described throughout Sambrook et al., (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York, and Ausubel et al., (1989) Current Protocols in Molecular Biology, Greene Publishing Associates and Wiley Interscience, New York, both incorporated herein in their entirety.

Depending on the host/vector system utilized, any of a number of suitable transcription and translation elements, including constitutive and inducible promoters, can be used in the expression vector. For example, when cloning in bacterial systems, inducible promoters such as pL of bacteriophage λ, plac, ptrp, ptac (ptrp-lac hybrid promoter) and the like can be used. When cloning in insect cell systems, promoters such as the baculovirus polyhedrin promoter can be used. When cloning in plant cell systems, promoters derived from the genome of plant cells, such as heat shock promoters; the promoter for the small subunit of RUBISCO; the promoter for the chlorophyll a/b binding protein) or from plant viruses (e.g., the 35S RNA promoter of CaMV; the coat protein promoter of TMV) can be used. When cloning in mammalian cell systems, promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter) can be used. When generating cell lines that contain multiple copies of the tyrosine kinase domain DNA, SV40-, BPV- and EBV-based vectors can be used with an appropriate selectable marker.

Adequate levels of expression of nuclear receptor LBDs can be obtained by the novel approaches described herein. High level expression in E. coli of ligand binding domains of TR and other nuclear receptors, including members of the steroid/thyroid receptor superfamily, such as the estrogen (ER), androgen (AR), mineralocorticoid (MR), progesterone (PR), RAR, RXR and vitamin D (VDR) receptors can also be achieved after review of the expression of a soluble GR polypeptide in bacteria, more preferably, E. coli disclosed herein. The GR polypeptides of the present invention, disclosed herein, can thus now provide a variety of host-expression vector systems. Yeast and other eukaryotic expression systems can be used with nuclear receptors that bind heat shock proteins since these nuclear receptors are generally more difficult to express in bacteria, with the exception of ER, which can be expressed in bacteria. In a preferred embodiment of the present invention, as disclosed in the Examples, a GR LBD is expressed in E. coli.

Representative nuclear receptors or their ligand binding domains have been cloned and sequenced, including human RARα, human RARγ, human RXRα, human RXRβ, human PPARα, human PPARβ or δ (delta), human PPARγ, human VDR, human ER (as described in Seielstad et al., (1995) Mol. Endocrinol. 9: 647-658), human GR, human PR, human MR, and human AR. The ligand binding domain of each of these nuclear receptors has been identified. Using this information in conjunction with the methods described herein, one of ordinary skill in the art can express and purify LBDs of any of the nuclear receptors, bind it to an appropriate ligand, and crystallize the nuclear receptor's LBD with a bound ligand, if desired.

Extracts of expressing cells are a suitable source of receptor for purification and preparation of crystals of the chosen receptor. To obtain such expression, a vector can be constructed in a manner similar to that employed for expression of the rat TR alpha (Apriletti et al., (1995) Protein Expression and Purification, 6: 368-370). The nucleotides encoding the amino acids encompassing the ligand binding domain of the receptor to be expressed can be inserted into an expression vector such as the one employed by Apriletti et al (1995). Stretches of adjacent amino acid sequences can be included if more structural information is desired.

The native and mutated nuclear receptors in general, and more particularly SR and GR polypeptides, and fragments thereof, of the present invention can also be chemically synthesized in whole or part using techniques that are known in the art (See, e.g., Creighton, (1983) Proteins: Structures and Molecular Principles, W.H. Freeman & Co., New York, incorporated herein in its entirety).

In a preferred embodiment, the present invention provides for the first time for the expression of a soluble GR polypeptide in bacteria, more preferably, E. coli, and subsequent purification thereof. Representative purification techniques are also disclosed in the Examples, particularly Example 1. The GR polypeptides of the present invention, disclosed herein, can thus now provide the ability to employ additional purification techniques for both liganded and unliganded NRs. Thus, it is envisioned, based upon the disclosure of the present invention, that purification of the unliganded or liganded NR, SR or GR receptor can be obtained by conventional techniques, such as hydrophobic interaction chromatography (HPLC), ion exchange chromatography (HPLC), and heparin affinity chromatography. To achieve higher purification for improved crystals of nuclear receptors it is sometimes preferable to ligand shift purify the nuclear receptor using a column that separates the receptor according to charge, such as an ion exchange or hydrophobic interaction column, and then bind the eluted receptor with a ligand. The ligand induces a change in the receptor's surface charge such that when re-chromatographed on the same column, the receptor then elutes at the position of the liganded receptor and is removed by the original column run with the unliganded receptor. Typically, saturating concentrations of ligand can be used in the column and the protein can be preincubated with the ligand prior to passing it over the column.

More recently developed methods involve engineering a “tag” such as with histidine placed on the end of the protein, such as on the amino terminus, and then using a nickel chelation column for purification. See Janknecht, (1991) Proc. Natl. Acad. Sci. U.S.A. 88: 8972-8976 (1991), incorporated by reference.

VII. Formation of NR, SR and GR Ligand Binding Domain Crystals

In one embodiment, the present invention provides crystals of GRα LBD. The crystals were obtained using the methodology disclosed in the Laboratory Examples. The GRα LBD crystals, which can be native crystals, derivative crystals or co-crystals, have hexagonal unit cells (a hexagonal unit cell is a unit cell wherein a=b≠c, and wherein α=β=90°, and γ=120°) and space group symmetry P6₁. There are two GRα LBD molecule in the asymmetric unit. In this GRα crystalline form, the unit cell has dimensions of a=b=126.014 Å, c=86.312 Å, and α=β=90°, and γ=120°. This crystal form can be formed in a crystallization reservoir as described in the Examples.

VII.A. Preparation of NR, SR and GR Crystals

The native and derivative co-crystals, and fragments thereof, disclosed in the present invention can be obtained by a variety of techniques, including batch, liquid bridge, dialysis, vapor diffusion and hanging drop methods (See, e.g., McPherson, (1982) Preparation and Analysis of Protein Crystals, John Wiley, New York; McPherson, (1990) Eur. J. Biochem. 189:1-23; Weber, (1991) Adv. Protein Chem. 41:1-36). In a preferred embodiment, the vapor diffusion and hanging drop methods are used for the crystallization of NR, SR and GR polypeptides and fragments thereof. A more preferred hanging drop method technique is disclosed in the Examples.

In general, native crystals of the present invention are grown by dissolving substantially pure NR, SR or GR polypeptide or a fragment thereof in an aqueous buffer containing a precipitant at a concentration just below that necessary to precipitate the protein. Water is removed by controlled evaporation to produce precipitating conditions, which are maintained until crystal growth ceases.

In one embodiment of the invention, native crystals are grown by vapor diffusion (See, e.g., McPherson, (1982) Preparation and Analysis of Protein Crystals, John Wiley, New York.; McPherson, (1990) Eur. J. Biochem. 189:1-23). In this method, the polypeptide/precipitant solution is allowed to equilibrate in a closed container with a larger aqueous reservoir having a precipitant concentration optimal for producing crystals. Generally, less than about 25 μL of NR, SR or GR polypeptide solution is mixed with an equal volume of reservoir solution, giving a precipitant concentration about half that required for crystallization. This solution is suspended as a droplet underneath a coverslip, which is sealed onto the top of the reservoir. The sealed container is allowed to stand, until crystals grow. Crystals generally form within two to six weeks, and are suitable for data collection within approximately seven to ten weeks. Of course, those of skill in the art will recognize that the above-described crystallization procedures and conditions can be varied.

VII.B. Preparation of Derivative Crystals

Derivative crystals of the present invention, e.g. heavy atom derivative crystals, can be obtained by soaking native crystals in mother liquor containing salts of heavy metal atoms. Such derivative crystals are useful for phase analysis in the solution of crystals of the present invention. In a preferred embodiment of the present invention, for example, soaking a native crystal in a solution containing methyl-mercury chloride provides derivative crystals suitable for use as isomorphous replacements in determining the X-ray crystal structure of a NR, SR or GR polypeptide. Additional reagents useful for the preparation of the derivative crystals of the present invention will be apparent to those of skill in the art after review of the disclosure of the present invention presented herein.

VII.C. Preparation of Co-Crystals

Co-crystals of the present invention can be obtained by soaking a native crystal in mother liquor containing compounds known or predicted to bind the LBD of a NR, SR or GR, or a fragment thereof. Alternatively, co-crystals can be obtained by co-crystallizing a NR, SR or GR LBD polypeptide or a fragment thereof in the presence of one or more compounds known or predicted to bind the polypeptide. In a preferred embodiment, as disclosed in the Examples, such a compound is dexamethasone.

VII.D. Solving a Crystal Structure of the Present Invention

Crystal structures of the present invention can be solved using a variety of techniques including, but not limited to, isomorphous replacement, anomalous scattering or molecular replacement methods. Computer software packages are also helpful in solving a crystal structure of the present invention. Applicable software packages include but are not limited to the CCP4 package disclosed in the Examples, the X-PLOR™ program (Brünger, (1992) X-PLOR, Version 3.1. A System for X-ray Crystallography and NMR, Yale University Press, New Haven, Conn.; X-PLOR is available from Molecular Simulations, Inc., San Diego, Calif.), Xtal View (McRee, (1992) J. Mol. Graphics 10: 44-46; X-tal View is available from the San Diego Supercomputer Center). SHELXS 97 (Sheldrick (1990) Acta Ctyst. A46: 467; SHELX 97 is available from the Institute of Inorganic Chemistry, Georg-August-Universität, Göttingen, Germany), HEAVY (Terwilliger, Los Alamos National Laboratory) and SHAKE-AND-BAKE (Hauptman, (1997) Curr. Opin. Struct. Biol. 7: 672-80; Weeks et al., (1993) Acta Cryst. D49: 179; available from the Hauptman-Woodward Medical Research Institute, Buffalo, N.Y.) can be used. See also, Ducruix & Geige, (1992) Crystallization of Nucleic Acids and Proteins: A Practical Approach, IRL Press, Oxford, England, and references cited therein.

VIII. Characterization and Solution of a GRα Ligand Binding Domain Crystal

Referring now to FIG. 3A, the overall arrangement of the GR LBD dimer is depicted in a ribbon/worm diagram that was derived from the crystalline polypeptide of the present invention. The two GR LBDs are shown in white and gray worm representation. The TIF2 peptides TIF2 are shown in gray ribbon and two dexamethasone ligands DEX are shown in space filling. The N terminus and C terminus of each GR LBD are labeled with a C and N, respectively. There is an interface between the two LBDs at beta turns and beta strands.

Referring now to FIGS. 3B and 3C, two orientations of the GR/TIF2/DEX complex are depicted. In each figure, the TIF2 peptide TIF2 is shown in ribbon and the GR LBD is shown in worm. The AF2 helix AF2 of GR is shown in gray worm in each figure. The key structural elements helix 9 H9 and helix 3 H3 are indicated, as is the N terminus N. The DEX compound DEX is shown in dark gray shading. In FIGS. 3B and 3C, the interaction of helix 3 H3 and the AF2 helix AF2 with dexamethasone DEX can be seen.

Referring now to FIGS. 4A and 4B, the overlap of GR LBD with the LBDs of the AR and PR (FIGS. 4A and 4B, respectively) is depicted. The AR and PR are shown as a thin line, while the GR is shown as a thick line. Backbone Calpha atoms are also shown. This superposition is consistent with the sequence alignment approach taken in the design of the GR LBD polypeptide disclosed herein.

RMS deviation calculation results were as follows: GR PR AR GR 0.00 0.94 1.56 PR 0.94 0.00 1.34 AR 1.56 1.34 0.00 where in each of the three calculations, the RMS deviation was computed using 980 N, backbone C alpha, C, O atoms from 245 aligned residues. These 245 residues are GR:531-775, PR:686-987, 899-931 and AR:672-883, 885-917. Several GR and PR residues before helix-1 were omitted in the calculations, as was one residue at the C-terminus, to correspond to the shorter AR construct. One residue (PR:898 and AR:884) was also omitted in the 10-AF2 loop because of the deletion in GR. The RMS deviations suggest that the AR structure has diverged away from GR and PR, and graphical examination confirmed this at least qualitatively.

Referring now to FIG. 5, a sequence alignment of steroid receptors, particularly an alignment of the F602S GRα sequence with MR, PR, AR, ERα, and Erβ is depicted. Residues that lie within 5.0 angstroms of the ligand are identified with small square boxes around the one-letter amino acid code. The ligands used for this calculation are dexamethasone (for GR), progesterone (for PR), dihydrotestosterone (for AR), estradiol (for ERα) and genistein (for ERβ). The alpha-helices and beta-strands observed in the X-ray structures are identified by the larger boxes and captions. Note that the secondary structure of MR is not publicly known at this time, and is thus not annotated in the Figure. More than one structure is available for PR, AR, ERα and ERβ, and, in some cases, the alpha-helices have different endpoints in these different X-ray structures. The variation in the alpha-helices is indicated here by using boxes with thicker and thinner linewidths, where the thicker linewidth box encompasses residues that adopt the same secondary structure in all available X-ray structures, and thinner linewidth boxes encompass residues that adopt an alpha-helical structure in some but not all X-ray structures. The secondary structures were determined by graphical examination of the X-ray structures.

It is also noted that, within the ligand binding domains (LBDs), the sequence identity is as follows: TABLE 1 Sequence Identity of NR LBDs GR MR PR AR GR 100% 56% 54% 50% MR 56% 100% 55% 51% PR 54% 55% 100% 55% AR 50% 51% 55% 100% VIII.A Unique Structural Differences Between GRα and Other SRs

Even though the GR LBD shares over 50% sequence identity with PR and AR and fold into a similar three-layer helical sandwich (FIGS. 4A and 4B), there are a number of unique structural differences in their structures. The most distinct differences are noted in the extended strand between helices 1 and 3, and the position of helix 7. These differences contribute a unique shape of the binding pocket for each receptor (FIGS. 6A and 6B) and may thus provide a molecular basis for steroid specificity of these receptors. The detailed structural information about the GR LBD and the pocket provided herein can be further exploited to design receptor specific agonists or antagoinists.

VIII.B Dexamethasone

The ligand binding domain of GRα was co-crystallized with dexamethasone, which has the IUPAC name (11β, 16α)-9-fluoro-11β,17,21-trihydroxy-16α-methylpregna-1-4-diene-3,20-dione and is shown below.

Dexamethasone is an agonist of GRα and is useful for treatment of GRα-mediated diseases or conditions including inflammation, tissue rejection, auto-immunity, malignancies such as leukemias and lymphomas, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of the Th1/Th2 cytokine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, and Little's syndrome as well as many other conditions.

VIII.C. Characterization of the GRα Binding Pocket and Interactions Between GRα and Dexamethasone

Referring now to FIG. 6A, the GR ligand binding pocket is depicted schematically. The GR ligand binding pocket is shown in a worm representation and the pocket is shown with a white surface. The gross shape of the binding pocket is depicted here with a smooth surface that covers the available volume within the binding pocket. The available volume is mapped by placing the protein within a grid, and then checking, for each grid point, whether a spherical probe atom can fit at that point without bumping into the protein. The spacing of grid points was taken as 0.50 Å, and the radius of the probe atom was taken as 1.40 Å. Atoms in the protein were represented as spheres with a radius of 1.20 Å for hydrogen, 1.70 Å for carbon, 1.55 Å for nitrogen, 1.52 Å for oxygen and 1.80 Å for sulfur. These are esssentially the atomic radius values suggested by Bondi (A. Bondi, “van der Waals Volumes and Radii,” Journal of Physical Chemistry, 68, 441-451 (1964)). The protein was represented with all hydrogen atoms in order to handle its volume more accurately. These hydrogen atoms where added to obtain the protonation states expected at pH 7 using the MVP program. The MVP program adds hydrogens using standard geometry, and then refines the initial coordinates with energy minimization, holding all heavy atoms fixed. The “available” grid points are defined as those for which the probe sphere does not bump into any sphere corresponding to a protein atom. The smooth surface was then constructed over these available binding site grid points using the dot surface program of Connolly (Michael L. Connolly, “Solvent-Accessible Surfaces of Proteins and Nucleic Acids,” Science 221, 709-713 (1983)) with a probe radius of 1.30 ÅA. The protein chain is shown with a backbone ribbon depiction.

Referring now to FIG. 6B, electron density in the GR-dexamethasone interface is depicted. The electron density is calculated with Fo coefficiency and shown in a one sigma cutoff. The ligand DEX is in the center of the figure. Key residues L732, A605, R611, Q570, G567, N564, and F749 encircle ligand DEX. Ligand DEX displays a good spatial fit, with no overlaps and no apparent charge repulsions.

Referring now to FIG. 7, molecular interactions between the GR protein and the dexamethasone are depicted. There are 22 residues from GR involved in direct interactions with the dexamethasone, and the residues are Q570, L566, G567, L563, W600, L753, N564, F749, C736, 1747, M560, T739, Q642, Y735, L732, M646, M601, A605, F623, M604, L608, and R611.

VIII.D. Structural Mechanism of Improving Protein Solubility by the F602S Mutation

FIG. 8 is a wire frame diagram that provides a closer look at the F602S mutation. The F602 is lipophilic but resides in the hydrophilic environment, a situation that could destabilize the protein. The mutation of the phenylalanine (F) to the serine (S) allows the S602 side chain to make direct hydrogen bonds with two water molecules, shown as 1H₂O and 2H₂O in FIG. 8. Association distances of 2.416 and 4.036 are indicated between S602 and 1H₂O and 2H₂O, respectively. Other residues are also shown in interaction with 1H₂O and 2H₂O, and these include H726 (which is also coordinated with water molecule 1H₂O), Y764 (which is also coordinated with water molecules 1H₂O and 2H₂O), Y598 and W600. An association distance of 4.354 is shown between 1H₂O and H726; and an association distance of 3.286 is shown with Y764. An association distance of 3.157 is shown between 1H₂O and 2H₂O. It is envisioned that this complex hydrogen bond network initiated by the F602S mutation and the two water molecules improves the protein stability thus the solubility as well.

VIII.E. Generation of Easily-Solved NR, SR and GR Crystals

The present invention discloses a substantially pure GR LBD polypeptide in crystalline form. In a preferred embodiment, exemplified in the Figures and Laboratory Examples, GRα is crystallized with bound ligand. Crystals can be formed from NR, SR and GR LBD polypeptides that are usually expressed by a cell culture, such as E. coli. Bromo- and iodo-substitutions can be included during the preparation of crystal forms and can act as heavy atom substitutions in GR ligands and crystals of NRs, SRs and GRs. This method can be advantageous for the phasing of the crystal, which is a crucial, and sometimes limiting, step in solving the three-dimensional structure of a crystallized entity. Thus, the need for generating the heavy metal derivatives traditionally employed in crystallography can be eliminated. After the three-dimensional structure of a NR, SR or GR, or an NR, SR or GR LBD with or without a ligand bound is determined, the resultant three-dimensional structure can be used in computational methods to design synthetic ligands for NR, SR or GR and for other NR, SR or GR polypeptides. Further activity structure relationships can be determined through routine testing, using assays disclosed herein and known in the art.

IX. Uses of NR, SR and GR Crystals and the Three-Dimensional Structure of the Ligand Binding Domain of GRα

The solved crystal structure of the present invention is useful in the design of modulators of activity mediated by the glucocorticoid receptor and by other nuclear receptors. Evaluation of the available sequence data shows that GRα is particularly similar to MR, PR and AR. The GRα LBD has approximately 55%, 54% and 50% sequence identity to the MR, PR and AR LBDs, respectively. The GRβ amino acid sequence is identical to the GRα amino acid sequence for residues 1-726, but the remaining 16 residues in GRβ show no significant similarity to the remaining 51 residues in GRα.

The present GRα X-ray structure can also be used to build models for targets where no X-ray structure is available, such as with GRβ and MR. Indeed, a model for GRα using the available X-ray structures of PR and/or AR as templates was built and used by the present co-inventors to obtain a starting model for the molecular replacement calculation used in solving the X-ray structure of GRα disclosed herein. These models will be less accurate than X-ray structures, but can help in the design of compounds targeted for GRβ and MR, for example. Also, these models can aid the design of compounds to selectively modulate any desired subset of GRα, GRβ, MR, PR, AR and other related nuclear receptors.

IX.A. Design and Development of NR, SR and GR Modulators

The present invention, particularly the computational methods, can be used to design drugs for a variety of nuclear receptors, such as receptors for glucocorticoids (GRs), androgens (ARs), mineralocorticoids (MRs), progestins (PRs), estrogens (ERs), thyroid hormones (TRs), vitamin D (VDRs), retinoid (RARs and RXRs) and peroxisomal proliferators (PPARs). The present invention can also be applied to the “orphan receptors,” as they are structurally homologous in terms of modular domains and primary structure to classic nuclear receptors, such as steroid and thyroid receptors. The amino acid homologies of orphan receptors with other nuclear receptors ranges from very low (<15%) to in the range of 35% when compared to rat RARα and human TRβ receptors, for example.

The knowledge of the structure of the GRα ligand binding domain (LBD), an aspect of the present invention, provides a tool for investigating the mechanism of action of GRα and other NR, SR and GR polypeptides in a subject. For example, various computer modelleing programs, as described herein, can predict the binding of various ligand molecules to the LBD of GRβ, or another steroid receptor or, more generally, nuclear receptor. Upon discovering that such binding in fact takes place, knowledge of the protein structure then allows design and synthesis of small molecules that mimic the functional binding of the ligand to the LBD of GRα, and to the LBDs of other polypeptides. This is the method of “rational” drug design, further described herein.

Use of the isolated and purified GRα crystalline structure of the present invention in rational drug design is thus provided in accordance with the present invention. Additional rational drug design techniques are described in U.S. Pat. Nos. 5,834,228 and 5,872,011, incorporated herein in their entirety.

Thus, in addition to the compounds described herein, other sterically similar compounds can be formulated to interact with the key structural regions of an NR, SR or GR in general, or of GRα in particular. The generation of a structural functional equivalent can be achieved by the techniques of modeling and chemical design known to those of skill in the art and described herein. It will be understood that all such sterically similar constructs fall within the scope of the present invention.

IX.A. 1. Rational Drug Design

The three-dimensional structure of ligand-binding GRα is unprecedented and will greatly aid in the development of new synthetic ligands for NR, SR and GR polypeptides, such as GR agonists and antagonists, including those that bind exclusively to any one of the GR subtypes. In addition, NRs, SRs and GRs are well suited to modern methods, including three-dimensional structure elucidation and combinatorial chemistry, such as those disclosed in U.S. Pat. Nos. 5,463,564, and 6,236,946 incorporated herein by reference. Structure determination using X-ray crystallography is possible because of the solubility properties of NRs SRs and GRs. Computer programs that use crystallography data when practicing the present invention will enable the rational design of ligands to these receptors.

Programs such as RASMOL (Biomolecular Structures Group, Glaxo Wellcome Research & Development Stevenage, Hertfordshire, UK Version 2.6, August 1995, Version 2.6.4, December 1998, Copyright ©Roger Sayle 1992-1999) and Protein Explorer (Version 1.87, Jul. 3, 2001, ©Eric Martz, 2001 and available online at http://www.umass.edu/microbio/chime/explorer/index.htm) can be used with the atomic structural coordinates from crystals generated by practicing the invention or used to practice the invention by generating three-dimensional models and/or determining the structures involved in ligand binding. Computer programs such as those sold under the registered trademark INSIGHT II® and the programs GRASP (Nicholls et al., (1991) Proteins 11: 281) and SYBYL™ (available from Tripos, Inc. of St. Louis, Mo.) allow for further manipulations and the ability to introduce new structures. In addition, high throughput binding and bioactivity assays can be devised using purified recombinant protein and modern reporter gene transcription assays known to those of skill in the art in order to refine the activity of a designed ligand.

A method of identifying modulators of the activity of an NR, SR or GR polypeptide using rational drug design is thus provided in accordance with the present invention. The method comprises designing a potential modulator for an NR, SR or GR polypeptide of the present invention that will form non-covalent interactions with amino acids in the ligand binding pocket based upon the crystalline structure of the GRα LBD polypeptide; synthesizing the modulator; and determining whether the potential modulator modulates the activity of the NR, SR or GR polypeptide. In a preferred embodiment, the modulator is designed for an SR polypeptide. In a more preferred embodiment, the modulator is designed for a GRα polypeptide. Preferably, the GRα polypeptide comprises the amino acid sequence of any of SEQ ID NOs:2, 4, 6 and 8, and more preferably, the GRα LBD comprises the amino acid sequence of any of SEQ ID NOs:10, 12, 14, 16 and 31. The determination of whether the modulator modulates the biological activity of an NR, SR or GR polypeptide is made in accordance with the screening methods disclosed herein, or by other screening methods known to those of skill in the art. Modulators can be synthesized using techniques known to those of ordinary skill in the art.

In an alternative embodiment, a method of designing a modulator of an NR, SR or GR polypeptide in accordance with the present invention is disclosed comprising: (a) selecting a candidate NR, SR or GR ligand; (b) determining which amino acid or amino acids of an NR, SR or GR polypeptide interact with the ligand using a three-dimensional model of a crystallized GRα LBD; (c) identifying in a biological assay for NR, SR or GR activity a degree to which the ligand modulates the activity of the NR, SR or GR polypeptide; (d) selecting a chemical modification of the ligand wherein the interaction between the amino acids of the NR, SR or GR polypeptide and the ligand is predicted to be modulated by the chemical modification; (e) synthesizing a chemical compound with the selected chemical modification to form a modified ligand; (f) contacting the modified ligand with the NR, SR or GR polypeptide; (g) identifying in a biological assay for NR, SR or GR activity a degree to which the modified ligand modulates the biological activity of the NR, SR or GR polypeptide; and (h) comparing the biological activity of the NR, SR or GR polypeptide in the presence of modified ligand with the biological activity of the NR, SR or GR polypeptide in the presence of the unmodified ligand, whereby a modulator of an NR, SR or GR polypeptide is designed.

An additional method of designing modulators of an NR, SR or GR or an NR, SR or GR LBD can comprise: (a) determining which amino acid or amino acids of an NR, SR or GR LBD interacts with a first chemical moiety (at least one) of the ligand using a three dimensional model of a crystallized protein comprising an NR, SR or GR LBD in complex with a bound ligand and a co-activator; and (b) selecting one or more chemical modifications of the first chemical moiety to produce a second chemical moiety with a structure to either decrease or increase an interaction between the interacting amino acid and the second chemical moiety compared to the interaction between the interacting amino acid and the first chemical moiety. This is a general strategy only, however, and variations on this disclosed protocol would be apparent to those of skill in the art upon consideration of the present disclosure.

Once a candidate modulator is synthesized as described herein and as will be known to those of skill in the art upon contemplation of the present invention, it can be tested using assays to establish its activity as an agonist, partial agonist or antagonist, and affinity, as described herein. After such testing, a candidate modulator can be further refined by generating LBD crystals with the candidate modulator bound to the LBD. The structure of the candidate modulator can then be further refined using the chemical modification methods described herein for three dimensional models to improve the activity or affinity of the candidate modulator and make second generation modulators with improved properties, such as that of a super agonist or antagonist, as described herein.

IX.A.2. Methods for Using the GRα LBD Structural Coordinates For Molecular Design

For the first time, the present invention permits the use of molecular design techniques to design, select and synthesize chemical entities and compounds, including modulatory compounds, capable of binding to the ligand binding pocket or an accessory binding site of an NR, SR or GR and an NR, SR or GR LBD, in whole or in part. Correspondingly, the present invention also provides for the application of similar techniques in the design of modulators of any NR, SR or GR polypeptide.

In accordance with a preferred embodiment of the present invention, the structure coordinates of a crystalline GRα LBD can be used to design compounds that bind to a GR LBD (more preferably a GRα LBD) and alter the properties of a GR LBD (for example, the dimerization ability, ligand binding ability or effect on transcription) in different ways. One aspect of the present invention provides for the design of compounds that can compete with natural or engineered ligands of a GR polypeptide by binding to all, or a portion of, the binding sites on a GR LBD. The present invention also provides for the design of compounds that can bind to all, or a portion of, an accessory binding site on a GR that is already binding a ligand. Similarly, non-competitive agonists/ligands that bind to and modulate GR LBD activity, whether or not it is bound to another chemical entity, and partial agonists and antagonists can be designed using the GR LBD structure coordinates of this invention.

A second design approach is to probe an NR, SR or GR or an NR, SR or GR LBD (preferably a GRα or GRα LBD) crystal with molecules comprising a variety of different chemical entities to determine optimal sites for interaction between candidate NR, SR or GR or NR, SR or GR LBD modulators and the polypeptide. For example, high resolution X-ray diffraction data collected from crystals saturated with solvent allows the determination of the site where each type of solvent molecule adheres. Small molecules that bind tightly to those sites can then be designed and synthesized and tested for their an NR, SR or GR modulator activity. Representative designs are also disclosed in published PCT application WO 99/26966.

Once a computationally-designed ligand is synthesized using the methods of the present invention or other methods known to those of skill in the art, assays can be used to establish its efficacy of the ligand as a modulator of NR, SR or GR (preferably GRα) activity. After such assays, the ligands can be further refined by generating intact NR, SR or GR, or NR, SR or GR LBD, crystals with a ligand bound to the LBD. The structure of the ligand can then be further refined using the chemical modification methods described herein and known to those of skill in the art, in order to improve the modulation activity or the binding affinity of the ligand. This process can lead to second generation ligands with improved properties.

Ligands also can be selected that modulate NR, SR or GR responsive gene transcription by the method of altering the interaction of co-activators and co-repressors with their cognate NR, SR or GR. For example, agonistic ligands can be selected that block or dissociate a co-repressor from interacting with a GR, and/or that promote binding or association of a co-activator. Antagonistic ligands can be selected that block co-activator interaction and/or promote co-repressor interaction with a target receptor. Selection can be done via binding assays that screen for designed ligands having the desired modulatory properties. Preferably, interactions of a GRα polypeptide are targeted. A suitable assay for screening that can be employed, mutatis mutandis in the present invention, as described in Oberfield, J. L., et al., Proc Natl Acad Sci USA. (1999) May 25; 96(11):6102-6, incorporated herein in its entirety by reference. Other examples of suitable screening assays for GR function include an in vitro peptide binding assay representing ligand-induced interaction with coactivator (Zhou, et al., (1998) Mol. Endocrinol. 12: 1594-1604; Parks et al., (1999) Science 284: 1365-1368) or a cell-based reporter assay related to transcription from a GRE (reviewed in Jenkins et al., (2001) Trends Endocrinol. Metab. 12: 122-126) or a cell-based reporter assay related to repression of genes driven via NF-kB. DeBosscher et al., (2000) Proc Natl Acad Sci USA. 97: 3919-3924.

IX.A.3. Methods of Designing NR, SR or GR LBD Modulator Compounds

Knowledge of the three-dimensional structure of the GR LBD complex of the present invention can facilitate a general model for modulator (e.g. agonist, partial agonist, antagonist and partial antagonist) design. Other ligand-receptor complexes belonging to the nuclear receptor superfamily can have a ligand binding pocket similar to that of GR and therefore the present invention can be employed in agonist/antagonist design for other members of the nuclear receptor superfamily and the steroid receptor subfamily. Examples of suitable receptors include those of the NR superfamily and those of the SR subfamily.

The design of candidate substances, also referred to as “compounds” or “candidate compounds”, that bind to or inhibit NR, SR or GR LBD-mediated activity according to the present invention generally involves consideration of two factors. First, the compound must be capable of physically and structurally associating with a NR, SR or GR LBD. Non-covalent molecular interactions important in the association of a NR, SR or GR LBD with its substrate include hydrogen bonding, van der Waals interactions and hydrophobic interactions.

The interaction between an atom of a LBD amino acid and an atom of an LBD ligand can be made by any force or attraction described in nature. Usually the interaction between the atom of the amino acid and the ligand will be the result of a hydrogen bonding interaction, charge interaction, hydrophobic interaction, van der Waals interaction or dipole interaction. In the case of the hydrophobic interaction it is recognized that this is not a per se interaction between the amino acid and ligand, but rather the usual result, in part, of the repulsion of water or other hydrophilic group from a hydrophobic surface. Reducing or enhancing the interaction of the LBD and a ligand can be measured by calculating or testing binding energies, computationally or using thermodynamic or kinetic methods as known in the art.

Second, the compound must be able to assume a conformation that allows it to associate with a NR, SR or GR LBD. Although certain portions of the compound will not directly participate in this association with a NR, SR or GR LBD, those portions can still influence the overall conformation of the molecule. This, in tum, can have a significant impact on potency. Such conformational requirements include the overall three-dimensional structure and orientation of the chemical entity or compound in relation to all or a portion of the binding site, e.g., the ligand binding pocket or an accessory binding site of a NR, SR or GR LBD, or the spacing between functional groups of a compound comprising several chemical entities that directly interact with a NR, SR or GR LBD.

Chemical modifications will often enhance or reduce interactions of an atom of a LBD amino acid and an atom of an LBD ligand. Steric hinderance can be a common means of changing the interaction of a LBD binding pocket with an activation domain. Chemical modifications are preferably introduced at C—H, C— and C—OH positions in a ligand, where the carbon is part of the ligand structure that remains the same after modification is complete. In the case of C—H, C could have 1, 2 or 3 hydrogens, but usually only one hydrogen will be replaced. The H or OH can be removed after modification is complete and replaced with a desired chemical moiety.

The potential modulatory or binding effect of a chemical compound on a NR, SR or GR LBD can be analyzed prior to its actual synthesis and testing by the use of computer modeling techniques that employ the coordinates of a crystalline GRα LBD polypeptide of the present invention. If the theoretical structure of the given compound suggests insufficient interaction and association between it and a NR, SR or GR LBD, synthesis and testing of the compound is obviated. However, if computer modeling indicates a strong interaction, the molecule can then be synthesized and tested for its ability to bind and modulate the activity of a NR, SR or GR LBD. In this manner, synthesis of unproductive or inoperative compounds can be avoided.

A modulatory or other binding compound of a NR, SR or GR LBD polypeptide (preferably a GRα LBD) can be computationally evaluated and designed via a series of steps in which chemical entities or fragments are screened and selected for their ability to associate with an individual binding site or other area of a crystalline GRα LBD polypeptide of the present invention and to interact with the amino acids disposed in the binding sites.

Interacting amino acids forming contacts with a ligand and the atoms of the interacting amino acids are usually 2 to 4 angstroms away from the center of the atoms of the ligand. Generally these distances are determined by computer as discussed herein and in McRee (McRee, (1993) Practical Protein Crystallography, Academic Press, New York), however distances can be determined manually once the three dimensional model is made. More commonly, the atoms of the ligand and the atoms of interacting amino acids are 3 to 4 angstroms apart. A ligand can also interact with distant amino acids, after chemical modification of the ligand to create a new ligand. Distant amino acids are generally not in contact with the ligand before chemical modification. A chemical modification can change the structure of the ligand to make as new ligand that interacts with a distant amino acid usually at least 4.5 angstroms away from the ligand. Often distant amino acids will not line the surface of the binding cavity for the ligand, as they are too far away from the ligand to be part of a pocket or surface of the binding cavity.

A variety of methods can be used to screen chemical entities or fragments for their ability to associate with an NR, SR or GR LBD and, more particularly, with the individual binding sites of an NR, SR or GR LBD, such as ligand binding pocket or an accessory binding site. This process can begin by visual inspection of, for example, the ligand binding pocket on a computer screen based on the GRα LBD atomic coordinates in Table 4, as described herein. Selected fragments or chemical entities can then be positioned in a variety of orientations, or docked, within an individual binding site of a GRα LBD as defined herein above. Docking can be accomplished using software programs such as those available under the tradenames QUANTA™ (Molecular Simulations Inc., San Diego, Calif.) and SYBYL™ (Tripos, Inc., St. Louis, Mo.), followed by energy minimization and molecular dynamics with standard molecular mechanics forcefields, such as CHARM (Brooks et al., (1983) J. Comp. Chem., 8: 132) and AMBER 5 (Case et al., (1997), AMBER 5, University of California, San Francisco; Pearlman et al., (1995) Comput. Phys. Commun. 91: 1-41).

Specialized computer programs can also assist in the process of selecting fragments or chemical entities. These include:

1. GRID™ program, version 17 (Goodford, (1985) J. Med. Chem. 28: 849-57), which is available from Molecular Discovery Ltd., Oxford, UK;

2. MCSS™ program (Miranker & Karplus, (1991) Proteins 11: 29-34), which is available from Molecular Simulations, Inc., San Diego, Calif.;

3. AUTODOCK™ 3.0 program (Goodsell & Olsen, (1990) Proteins 8: 195-202), which is available from the Scripps Research Institute, La Jolla, Calif.;

4. DOCK™ 4.0 program (Kuntz et al., (1992) J. Mol. Biol. 161: 269-88), which is available from the University of California, San Francisco, Calif.;

5. FLEX-X™ program (See, Rarey et al., (1996) J. Comput. Aid. Mol. Des. 10:41-54), which is available from Tripos, Inc., St. Louis, Mo.;

6. MVP program (Lambert, (1997) in Practical Application of Computer-Aided Drug Design, (Charifson, ed.) Marcel-Dekker, New York, pp. 243-303); and

7. LUDI™ program (Bohm, (1992) J. Comput. Aid. Mol. Des., 6: 61-78), which is available from Molecular Simulations, Inc., San Diego, Calif.

Once suitable chemical entities or fragments have been selected, they can be assembled into a single compound or modulator. Assembly can proceed by visual inspection of the relationship of the fragments to each other on the three-dimensional image displayed on a computer screen in relation to the structure coordinates of a GRα LBD. Manual model building using software such as QUANTA™ or SYBYL™ typically follows.

Useful programs to aid one of ordinary skill in the art in connecting the individual chemical entities or fragments include:

1. CAVEAT™ program (Bartlett et al., (1989) Special Pub., Royal Chem. Soc. 78: 182-96), which is available from the University of California, Berkeley, Calif.;

2. 3D Database systems, such as MACCS-3D™ system program, which is available from MDL Information Systems, San Leandro, Calif. This area is reviewed in Martin, (1992) J. Med. Chem. 35: 2145-54; and

3. HOOK™ program (Eisen et al., (1994). Proteins 19: 199-221), which is available from Molecular Simulations, Inc., San Diego, Calif.

Instead of proceeding to build a GR LBD modulator (preferably a GRα LBD modulator) in a step-wise fashion one fragment or chemical entity at a time as described above, modulatory or other binding compounds can be designed as a whole or de novo using the structural coordinates of a crystalline GRα LBD polypeptide of the present invention and either an empty binding site or optionally including some portion(s) of a known modulator(s). Applicable methods can employ the following software programs:

1. LUDI™ program (Bohm, (1992) J. Comput. Aid. Mol. Des., 6: 61-78), which is available from Molecular Simulations, Inc., San Diego, Calif.;

2. LEGEND™ program (Nishibata & Itai, (1991) Tetrahedron 47: 8985); and

3. LEAPFROG™, which is available from Tripos Associates, St. Louis, Mo.

Other molecular modeling techniques can also be employed in accordance with this invention. See, e.g., Cohen et al., (1990) J. Med. Chem. 33: 883-94. See also, Navia & Murcko, (1992) Curr. Opin. Struc. Biol. 2: 202-10; U.S. Pat. No. 6,008,033, herein incorporated by reference.

Once a compound has been designed or selected by the above methods, the efficiency with which that compound can bind to a NR, SR or GR LBD can be tested and optimized by computational evaluation. By way of particular example, a compound that has been designed or selected to function as a NR, SR or GR LBD modulator should also preferably traverse a volume not overlapping that occupied by the binding site when it is bound to its native ligand. Additionally, an effective NR, SR or GR LBD modulator should preferably demonstrate a relatively small difference in energy between its bound and free states (i.e., a small deformation energy of binding). Thus, the most efficient NR, SR and GR LBD modulators should preferably be designed with a deformation energy of binding of not greater than about 10 kcal/mole, and preferably, not greater than 7 kcal/mole. It is possible for NR, SR and GR LBD modulators to interact with the polypeptide in more than one conformation that is similar in overall binding energy. In those cases, the deformation energy of binding is taken to be the difference between the energy of the free compound and the average energy of the conformations observed when the modulator binds to the polypeptide.

A compound designed or selected as binding to an NR, SR or GR polypeptide (preferably a GRα LBD polypeptide) can be further computationally optimized so that in its bound state it would preferably lack repulsive electrostatic interaction with the target polypeptide. Such non-complementary (e.g., electrostatic) interactions include repulsive charge-charge, dipole-dipole and charge-dipole interactions. Specifically, the sum of all electrostatic interactions between the modulator and the polypeptide when the modulator is bound to an NR, SR or GR LBD preferably make a neutral or favorable contribution to the enthalpy of binding.

Specific computer software is available in the art to evaluate compound deformation energy and electrostatic interaction. Examples of programs designed for such uses include:

1. Gaussian 98™, which is available from Gaussian, Inc., Pittsburgh, Pa.;

2. AMBER™ program, version 6.0, which is available from the University of California at San Francisco;

3. QUANTA™ program, which is available from Molecular Simulations, Inc., San Diego, Calif.;

4. CHARMm® program, which is available from Molecular Simulations, Inc., San Diego, Calif.; and

4. Insight II® program, which is available from Molecular Simulations, Inc., San Diego, Calif.

These programs can be implemented using a suitable computer system. Other hardware systems and software packages will be apparent to those skilled in the art after review of the disclosure of the present invention presented herein.

Once an NR, SR or GR LBD modulating compound has been optimally selected or designed, as described above, substitutions can then be made in some of its atoms or side groups in order to improve or modify its binding properties. Generally, initial substitutions are conservative, i.e., the replacement group will have approximately the same size, shape, hydrophobicity and charge as the original group. It should, of course, be understood that components known in the art to alter conformation are preferably avoided. Such substituted chemical compounds can then be analyzed for efficiency of fit to an NR, SR or GR LBD binding site using the same computer-based approaches described in detail above.

IX.B. Distinguishing Between GR Subtypes and Between NRs

The present invention also is applicable to generating new synthetic ligands to distinguish nuclear receptor subtypes. As described herein, modulators can be generated that distinguish between subtypes, thereby allowing the generation of either tissue specific or function specific synthetic ligands. For instance, the GRα gene can be translated from its mRNA by alternative initiation from an internal ATG codon (Yudt & Cidlowski (2001) Molec. Endocrinol. 15: 1093-1103). This codon codes for methionine at position 27 and translation from this position produces a slightly smaller protein. These two isoforms, translated from the same gene, are referred to as GR-A and GR-B. It has been shown in a cellular system that the shorter GR-B form is more effective in initiating transcription from a GRE compared to GR-A. Additionally, another form of GR, called GRβ is produced by an alternative splicing event. The GRβ protein differs from GRα at the very C-terminus, where the final 50 amino acids are replaced with a 15 amino acid segment. These two isoforms are 100% identical up to amino acid 727. No sequence similarity exists between GRα and GRβ at the C-terminus beyond position 727. GRβ has been shown to be a dominant negative regulator of GRα-mediated gene transcription (Oakley, Sar & Cidlowski (1996) J. Biol. Chem. 271: 9550-9559). It has been suggested that some of the tissue specific effects observed with glucocorticoid treatment may in part be due to the presence of varying amounts of isoform in certain cell-types. This method is also applicable to any other subfamily so organized.

The present invention discloses the ability to generate new synthetic ligands to distinguish between GR subtypes. As described herein, computer-designed ligands (i.e. candidate modulators and modulators) can be generated that distinguish between GR subtypes, thereby allowing the generation of either tissue specific or function specific ligands. The atomic structural coordinates disclosed in the present invention reveal structural details unique to GRα. These structural details can be exploited when a novel ligand is designed using the methods of the present invention or other ligand design methods known in the art. The structural features that differentiate, for example, a GRα from a GRβ can be targeted in ligand design. Thus, for example, a ligand can be designed that will recognize GRα, while not interacting with other GRs or even with moieties having similar structural features. Prior to the disclosure of the present invention, the ability to target a GR subtype was unattainable.

The present invention also pertains to a method for designing an agonist or modulator with desired levels of activity on at least two subtypes, GRα and GRβ. In a preferred embodiment, the method comprises obtaining atomic coordinates for structures of the GRα and/or GRβ ligand binding domains. The structures can comprise GRα and GRβ, each bound to various different ligands, and also can comprise structures where no ligand is present. The structures can also comprise models where a compound has been docked into a particular GR using a molecular docking procedure, such as the MVP program disclosed herein. Optionally, the structures are rotated and translated so as to superimpose corresponding Cα or backbone atoms; this facilitates the comparison of structures.

The GRα and GRβ structures can also be compared using a computer graphics system to identify regions of the ligand binding site that have similar shape and electrostatic character, and to identify regions of the ligand binding site that are narrowed or constricted in one or both of the GRs, particularly as compared to other NRs. Since these three GRs are subject to conformational changes, attention is paid to the range of motion observed for each protein atom over the whole collection of structures. The ligand structures, including both those determined by X-ray crystallography and those modeled using molecular docking procedures, can be examined using a computer graphics system to identify ligands where a chemical modification could increase or decrease binding to a particular GR, or decrease activity against a particular GR. Additionally or alternatively, the chemical modification can introduce a group into a volume that is normally occupied by an atom of that GR.

Optionally, to selectively decrease activity against a particular GR, the chemical modification can be made so as to occupy volume that is normally occupied by atoms of that particular GR, but not by atoms of the other GRs. To increase activity against a particular GR, a chemical modification can be made that improves interactions with that particular GR. To selectively increase activity against a particular GR, a chemical modification can be made that improves the interactions with that particular GR, but does not improve the interactions with the other GRs. Other design principles can also be used to increase or decrease activity on a particular GR.

Thus, various possible compounds and chemical modfications can be considered and compared graphically, and with molecular modeling tools, for synthetic feasibility and likelihood of achieving the desired profile of activation of GRα and GRβ. Compounds that appear synthetically feasible and that have a good likelihood of achieving the desired profile are synthesized. The compounds can then be tested for binding and/or activation of GRα and GRβ, and tested for their overall biological effect.

A method of identifying a NR modulator that selectively modulates the biological activity of one NR compared to GRα is also disclosed. In one embodiment, the method comprises: (a) providing an atomic structure coordinate set describing a GRα ligand binding domain structure and at least one other atomic structure coordinate set describing a NR ligand binding domain, each ligand binding domain comprising a ligand binding site; (b) comparing the atomic structure coordinate sets to identify at least one diference between the sets; (c) designing a candidate ligand predicted to interact with the difference of step (b); (d) synthesizing the candidate ligand; and (e) testing the synthesized candidate ligand for an ability to selectively modulate a NR as compared to GRα, whereby a NR modulator that selectively modulates the biological activity NR compared to GRα is identified.

Preferably, the GRα atomic structure coordinate set is the atomic structure coordinate set shown in Table 4. Optionally, the NR is selected from the group consisting of MR, PR, AR, GRβ and isoforms thereof that have ligands that also bind GRα.

IX.C. Method of Screening for Chemical and Biological Modulators of the Biological Activity of an NR, SR or GR

A candidate substance identified according to a screening assay of the present invention has an ability to modulate the biological activity of an NR, SR or GR or an NR, SR or GR LBD polypeptide. In a preferred embodiment, such a candidate compound can have utility in the treatment of disorders and/or conditions and/or biological events associated with the biological activity of an NR, SR or GR or an NR, SR or GR LBD polypeptide, including transcription modulation.

In a cell-free system, the method comprises the steps of establishing a control system comprising a GRα polypeptide and a ligand which is capable of binding to the polypeptide; establishing a test system comprising a GRα polypeptide, the ligand, and a candidate compound; and determining whether the candidate compound modulates the activity of the polypeptide by comparison of the test and control systems. A representative ligand can comprise dexamethasone or other small molecule, and in this embodiment, the biological activity or property screened can include binding affinity or transcription regulation. The GRα polypeptide can be in soluble or crystalline form.

In another embodiment of the invention, a soluble or a crystalline form of a GRα polypeptide or a catalytic or immunogenic fragment or oligopeptide thereof, can be used for screening libraries of compounds in any of a variety of drug screening techniques. The fragment employed in such a screening can be affixed to a solid support. The formation of binding complexes, between a soluble or a crystalline GRα polypeptide and the agent being tested, will be detected. In a preferred embodiment, the soluble or crystalline GRα polypeptide has an amino acid sequence of any of SEQ ID NOs:4, 6, 8 or 10. When a GRα LBD polypeptide is employed, a preferred embodiment will include a soluble or a crystalline GRα polypeptide having the amino acid sequence of any of SEQ ID NOs:12, 14, 16 or 31.

Another technique for drug screening which can be used provides for high throughput screening of compounds having suitable binding affinity to the protein of interest as described in published PCT application WO 84/03564, herein incorporated by reference. In this method, as applied to a soluble or crystalline polypeptide of the present invention, large numbers of different small test compounds are synthesized on a solid substrate, such as plastic pins or some other surface. The test compounds are reacted with the soluble or crystalline polypeptide, or fragments thereof. Bound polypeptide is then detected by methods known to those of skill in the art. The soluble or crystalline polypeptide can also be placed directly onto plates for use in the aforementioned drug screening techniques.

In yet another embodiment, a method of screening for a modulator of an NR, SR or GR or an NR, SR or GR LBD polypeptide comprises: providing a library of test samples; contacting a soluble or a crystalline form of an NR, SR or GR or a soluble or crystalline form of an NR, SR or GR LBD polypeptide with each test sample; detecting an interaction between a test sample and a soluble or a crystalline form of an NR, SR or GR or a soluble or a crystalline form of an NR, SR or GR LBD polypeptide; identifying a test sample that interacts with a soluble or a crystalline form of an NR, SR or GR or a soluble or a crystalline form of an NR, SR or GR LBD polypeptide; and isolating a test sample that interacts with a soluble or a crystalline form of an NR, SR or GR or a soluble or a crystalline form of an NR, SR or GR LBD polypeptide.

In each of the foregoing embodiments, an interaction can be detected spectrophotometrically, radiologically, calorimetrically or immunologically. An interaction between a soluble or a crystalline form of an NR, SR or GR or a soluble or a crystalline form of an NR, SR or GR LBD polypeptide and a test sample can also be quantified using methodology known to those of skill in the art.

In accordance with the present invention there is also provided a rapid and high throughput screening method that relies on the methods described above. This screening method comprises separately contacting each of a plurality of substantially identical samples with a soluble or a crystalline form of an NR, SR or GR or a soluble or a crystalline form of an NR, SR or GR LBD and detecting a resulting binding complex. In such a screening method the plurality of samples preferably comprises more than about 10⁴ samples, or more preferably comprises more than about 5×10⁴ samples.

In another embodiment, a method for identifying a substance that modulates GR LBD function is also provided. In a preferred embodiment, the method comprises: (a) isolating a GR polypeptide of the present invention; (b) exposing the isolated GR polypeptide to a plurality of substances; (c) assaying binding of a substance to the isolated GR polypeptide; and (d) selecting a substance that demonstrates specific binding to the isolated GR LBD polypeptide. By the term “exposing the GR polypeptide to a plurality of substances”, it is meant both in pools and as mutiple samples of “discrete” pure substances.

IX.D. Method of Identifying Compounds Which Inhibit Ligand Binding

In one aspect of the present invention, an assay method for identifying a compound that inhibits binding of a ligand to an NR, SR or GR polypeptide is disclosed. A ligand, such as dexamethasone (which associates with at least GR), can be used in the assay method as the ligand against which the inhibition by a test compound is gauged. In the following discussion of Section IX.D., it will be understood that although GR is used as an example, the method is equally applicable to any of NR, SR or GR polypeptide The method comprises (a) incubating a GR polypeptide with a ligand in the presence of a test inhibitor compound; (b) determining an amount of ligand that is bound to the GR polypeptide, wherein decreased binding of ligand to the GR polypeptide in the presence of the test inhibitor compound relative to binding in the absence of the test inhibitor compound is indicative of inhibition; and (c) identifying the test compound as an inhibitor of ligand binding if decreased ligand binding is observed. Preferably, the ligand is dexamethasone.

In another aspect of the present invention, the disclosed assay method can be used in the structural refinement of candidate GR inhibitors. For example, multiple rounds of optimization can be followed by gradual structural changes in a strategy of inhibitor design. A strategy such as this is made possible by the disclosure of the atomic coordinates of the GRα LBD.

X. Design, Preparation and Structural Analysis of Additional NR, SR and GR Polypeptides and NR, SR and GR LBD Mutants and Structural Equivalents

The present invention provides for the generation of NR, SR and GR polypeptides and NR, SR or GR mutants (preferably GRα and GRα LBD mutants), and the ability to solve the crystal structures of those that crystallize. Indeed, a GRα LBD havingfa point mutation was crystallized and solved in one aspect of the present invention. Thus, an aspect of the present invention involves the use of both targeted and random mutagenesis of the GR gene for the production of a recombinant protein with improved or desired characteristics for the purpose of crystallization, characterization of biologically relevant protein-protein interactions, and compound screening assays, or for the production of a recombinant protein having other desirable characteristic(s). Polypeptide products produced by the methods of the present invention are also disclosed herein.

The structure coordinates of a NR, SR or GR LBD provided in accordance with the present invention also facilitate the identification of related proteins or enzymes analogous to GRα in function, structure or both, (for example, a GRβ which can lead to novel therapeutic modes for treating or preventing a range of disease states. More particularly, through the provision of the mutagenesis approaches as well as the three-dimensional structure of a GRα LBD disclosed herein, desirable sites for mutation are identified.

X.A. Sterically Similar Compounds

A further aspect of the present invention is that sterically similar compounds can be formulated to mimic the key portions of an NR, SR or GR LBD structure. Such compounds are functional equivalents. The generation of a structural functional equivalent can be achieved by the techniques of modeling and chemical design known to those of skill in the art and described herein. Modeling and chemical design of NR, SR or GR and NR, SR or GR LBD structural equivalents can be based on the structure coordinates of a crystalline GRα LBD polypeptide of the present invention. It will be understood that all such sterically similar constructs fall within the scope of the present invention.

X.B. NR, SR and GR Polypeptides The generation of chimeric GR polypeptides is also an aspect of the present invention. Such a chimeric polypeptide can comprise an NR, SR or GR LBD polypeptide or a portion of an NR, SR or GR LBD, (e.g. a GRα LBD) that is fused to a candidate polypeptide or a suitable region of the candidate polypeptide, for example GRβ. Throughout the present disclosure it is intended that the term “mutant” encompass not only mutants of an NR, SR or GR LBD polypeptide but chimeric proteins generated using an NR, SR or GR LBD as well. It is thus intended that the following discussion of mutant NR, SR and GR LBDs apply mutatis mutandis to chimeric NR, SR and GR polypeptides and NR, SR and GR LBD polypeptides and to structural equivalents thereof.

In accordance with the present invention, a mutation can be directed to a particular site or combination of sites of a wild-type NR, SR or GR LBD. For example, an accessory binding site or the binding pocket can be chosen for mutagenesis. Similarly, a residue having a location on, at or near the surface of the polypeptide can be replaced, resulting in an altered surface charge of one or more charge units, as compared to the wild-type NR, SR or GR and NR, SR or GR LBDs. Alternatively, an amino acid residue in an NR, SR or GR or an NR, SR or GR LBD can be chosen for replacement based on its hydrophilic or hydrophobic characteristics.

Such mutants can be characterized by any one of several different properties, i.e. a “desired” or “predetermined” characteristic as compared with the wild type NR, SR or GR LBD. For example, such mutants can have an altered surface charge of one or more charge units, or can have an increase in overall stability. Other mutants can have altered substrate specificity in comparison with, or a higher specific activity than, a wild-type NR, SR or GR or an NR, SR or GR LBD.

NR, SR or GR and NR, SR or GR LBD mutants of the present invention can be generated in a number of ways. For example, the wild-type sequence of an NR, SR or GR or an NR, SR or GR LBD can be mutated at those sites identified using this invention as desirable for mutation, by means of oligonucleotide-directed mutagenesis or other conventional methods, such as deletion. Alternatively, mutants of an NR, SR or GR or an NR, SR or GR LBD can be generated by the site-specific replacement of a particular amino acid with an unnaturally occurring amino acid. In addition, NR, SR or GR or NR, SR or GR LBD mutants can be generated through replacement of an amino acid residue, for example, a particular cysteine or methionine residue, with selenocysteine or selenomethionine. This can be achieved by growing a host organism capable of expressing either the wild-type or mutant polypeptide on a growth medium depleted of either natural cysteine or methionine (or both) but enriched in selenocysteine or selenomethionine (or both).

As disclosed in the Examples presented below, mutations can be introduced into a DNA sequence coding for an NR, SR or GR or an NR, SR or GR LBD using synthetic oligonucleotides. These oligonucleotides contain nucleotide sequences flanking the desired mutation sites. Mutations can be generated in the full-length DNA sequence of an NR, SR or GR or an NR, SR or GR LBD or in any sequence coding for polypeptide fragments of an NR, SR or GR or an NR, SR or GR LBD.

According to the present invention, a mutated NR, SR or GR or NR, SR or GR LBD DNA sequence produced by the methods described above, or any alternative methods known in the art, can be expressed using an expression vector. An expression vector, as is well known to those of skill in the art, typically includes elements that permit autonomous replication in a host cell independent of the host genome, and one or more phenotypic markers for selection purposes. Either prior to or after insertion of the DNA sequences surrounding the desired NR, SR or GR or NR, SR or GR LBD mutant coding sequence, an expression vector also will include control sequences encoding a promoter, operator, ribosome binding site, translation initiation signal, and, optionally, a repressor gene or various activator genes and a signal for termination. In some embodiments, where secretion of the produced mutant is desired, nucleotides encoding a “signal sequence” can be inserted prior to an NR, SR or GR or an NR, SR or GR LBD mutant coding sequence. For expression under the direction of the control sequences, a desired DNA sequence must be operatively linked to the control sequences; that is, the sequence must have an appropriate start signal in front of the DNA sequence encoding the NR, SR or GR or NR, SR or GR LBD mutant, and the correct reading frame to permit expression of that sequence under the control of the control sequences and production of the desired product encoded by that NR, SR or GR or NR, SR or GR LBD sequence must be maintained.

After a review of the disclosure of the present invention presented herein, any of a wide variety of well-known available expression vectors can be useful to express a mutated coding sequence of this invention. These include for example, vectors consisting of segments of chromosomal, non-chromosomal and synthetic DNA sequences, such as various known derivatives of SV40, known bacterial plasmids, e.g., plasmids from E. coli including col E1, pCR1, pBR322, pMB9 and their derivatives, wider host range plasmids, e.g., RP4, phage DNAs, e.g., the numerous derivatives of phage λ, e.g., NM 989, and other DNA phages, e.g., M13 and filamentous single stranded DNA phages, yeast plasmids and vectors derived from combinations of plasmids and phage DNAs, such as plasmids which have been modified to employ phage DNA or other expression control sequences. In the preferred embodiments of this invention, vectors amenable to expression in a pET-based expression system are employed. The pET expression system is available from Novagen/Invitrogen, Inc., Carlsbad, Calif. Expression and screening of a polypeptide of the present invention in bacteria, preferably E. coli, is a preferred aspect of the present invention.

In addition, any of a wide variety of expression control sequences—sequences that control the expression of a DNA sequence when operatively linked to it—can be used in these vectors to express the mutated DNA sequences according to this invention. Such useful expression control sequences, include, for example, the early and late promoters of SV40 for animal cells, the lac system, the trp system the TAC or TRC system, the major operator and promoter regions of phage λ, the control regions of fd coat protein, all for E. coli, the promoter for 3-phosphoglycerate kinase or other glycolytic enzymes, the promoters of acid phosphatase, e.g., Pho5, the promoters of the yeast α-mating factors for yeast, and other sequences known to control the expression of genes of prokaryotic or eukaryotic cells or their viruses, and various combinations thereof.

A wide variety of hosts are also useful for producing mutated NR, SR or GR and NR, SR or GR LBD polypeptides according to this invention. These hosts include, for example, bacteria, such as E. coli, Bacillus and Streptomyces, fungi, such as yeasts, and animal cells, such as CHO and COS-1 cells, plant cells, insect cells, such as SF9 cells, and transgenic host cells. Expression and screening of a polypeptide of the present invention in bacteria, preferably E. coli, is a preferred aspect of the present invention.

It should be understood that not all expression vectors and expression systems function in the same way to express mutated DNA sequences of this invention, and to produce modified NR, SR or GR and NR, SR or GR LBD polypeptides or NR, SR or GR or NR, SR or GR LBD mutants. Neither do all hosts function equally well with the same expression system. One of skill in the art can, however, make a selection among these vectors, expression control sequences and hosts without undue experimentation and without departing from the scope of this invention. For example, an important consideration in selecting a vector will be the ability of the vector to replicate in a given host. The copy number of the vector, the ability to control that copy number, and the expression of any other proteins encoded by the vector, such as antibiotic markers, should also be considered.

In selecting an expression control sequence, a variety of factors should also be considered. These include, for example, the relative strength of the system, its controllability and its compatibility with the DNA sequence encoding a modified NR, SR or GR or NR, SR or GR LBD polypeptide of this invention, with particular regard to the formation of potential secondary and tertiary structures.

Hosts should be selected by consideration of their compatibility with the chosen vector, the toxicity of a modified polypeptide to them, their ability to express mature products, their ability to fold proteins correctly, their fermentation requirements, the ease of purification of a modified GR or GR LBD and safety. Within these parameters, one of skill in the art can select various vector/expression control system/host combinations that will produce useful amounts of a mutant polypeptide. A mutant polypeptide produced in these systems can be purified, for example, via the approaches disclosed in the Examples.

Once a mutation(s) has been generated in the desired location, such as an active site or dimerization site, the mutants can be tested for any one of several properties of interest, i.e. “desired” or “predetermined” positions. For example, mutants can be screened for an altered charge at physiological pH. This property can be determined by measuring the mutant polypeptide isoelectric point (pI) and comparing the observed value with that of the wild-type parent. Isoelectric point can be measured by gel-electrophoresis according to the method of Wellner (Wellner, (1971) Anal. Chem. 43: 597). A mutant polypeptide containing a replacement amino acid located at the surface of the enzyme, as provided by the structural information of this invention, can lead to an altered surface charge and an altered pI.

X.C. Generation of an Engineered NR, SR or GR or NR, SR or GR LBD Mutants

In another aspect of the present invention, a unique NR, SR or GR or NR, SR or GR LBD polypeptide is generated. Such a mutant can facilitate purification and the study of the structure and the ligand-binding abilities of a NR, SR or GR polypeptide. Thus, an aspect of the present invention involves the use of both targeted and random mutagenesis of the GR gene for the production of a recombinant protein with improved solution characteristics for the purpose of crystallization, characterization of biologically relevant protein-protein interactions, and compound screening assays , or for the production of a recombinant polypeptide having other characteristics of interest. Expression of the polypeptide in bacteria, preferably E. coli, is also an aspect of the present invention.

In one embodiment, targeted mutagenesis was performed using a sequence alignment of several nuclear receptors, primarily steroid receptors. Several residues that were hydrophobic in GR and hydrophilic in other receptors were chosen for mutagenesis. Most of these residues were predicted to be solvent exposed hydrophobic residues in GR. Therefore, mutations were made to change these hydrophobic residues to hydrophilic in attempt to improve the solubility and stability of E. coli-expressed GR LBD. Table 2 immediately below presents a list of mutations (for that were made and tested for expression in E. coli. TABLE 2 Mutations of the GR LBD (521-777) Gene for Testing Solution Solubility and Stability Single mutations Double mutations Triple mutations V552K L535T/V538S M691T/V702T/W712T W557S V552K/W557S F602S L636E/C638S F602D F602E L636E Y648Q W712S L741R F602Y F602T F602N F602C

Random mutagenesis can be performed on residues where a significant difference, hydrophobic versus hydrophilic, is observed between GR and other steroid receptors based on sequence alignment. Such positions can be randomized by oligo-directed or cassette mutagenesis. A GR LBD protein library can be sorted by an appropriate display system to select mutants with improved solution properties. Residues in GR that meet the criteria for such an approach include: V538, V552, W557, F602, L636, Y648, Y660, L685, M691, V702, W712, L733, and Y764. In addition, residues predicted to neighbor these positions could also be randomized.

In another embodiment, complete random mutagenesis can be performed on any residue within the context of the GR LBD. A method such as error incorporating PCR or chemical-based mutagenesis can be used to introduce mutations in an unbiased manner. These methods randomize the position of mutation as well as the nature of the mutated residue. A completely random GR LBD library can be screened for improved expression with the appropriate expression or display system. Ideally, the selection method should identify mutant proteins with increased expression, solubility, stability, and/or activity. A technique well suited for this purpose is the “peptides-on-plasmid” display system that utilizes the DNA-binding activity of the lac repressor (Lacl). GR, or another nuclear receptor LBD, can be expressed as a fusion to either Lacl or a fragment of Lacl, such as the “headpiece dimer”, that comprises the DNA-binding domain. Because the plasmid that expresses the fusion protein also comprises a lac operon binding site, the protein will be physically coupled to the plasmid. GR mutants that produce soluble protein can then be isolated using either the coactivator peptide- or ligand-binding activity of the receptor. Table 2A below shows mutations that were prepared using the Lacl-based “peptides-on-plasmids” technique with GR LBD. TABLE 2A Random Mutations of the GR LBD (521-777) Gene for Improving Solution Solubility and Stability Single Double mutations SEQ ID NO Mutations SEQ ID NO W557R 33 F602L/A580T 38 Q615L 34 L563F/G583C 39 Q615H 35 L664H/M752T 40 A574T 36 L563F/T744N 41 L620M 37

A method of modifying a test NR polypeptide is thus disclosed. The method can comprise: providing a test NR polypeptide sequence having a characteristic that is targeted for modification; aligning the test NR polypeptide sequence with at least one reference NR polypeptide sequence for which an X-ray structure is available, wherein the at least one reference NR polypeptide sequence has a characteristic that is desired for the test NR polypeptide; building a three-dimensional model for the test NR polypeptide using the three-dimensional coordinates of the X-ray structure(s) of the at least one reference polypeptide and its sequence alignment with the test NR polypeptide sequence; examining the three-dimensional model of the test NR polypeptide for differences with the at least one reference polypeptide that are associated with the desired characteristic; and mutating at least one amino acid residue in the test NR polypeptide sequence located at a difference identified above to a residue associated with the desired characteristic, whereby the test NR polypeptide is modified. By the term “associated with a desired characteristic” it is meant that a residue is found in the reference polypeptide at a point of difference wherein the difference provides a desired characteristic or phenotype in the reference polypeptide.

A method of altering the solubility of a test NR polypeptide is also disclosed in accordance with the present invention. In a preferred embodiment, the method comprises: (a) providing a reference NR polypeptide sequence and a test NR polypeptide sequence; (b) comparing the reference NR polypeptide sequence and the test NR polypeptide sequence to identify one or more residues in the test NR sequence that are more or less hydrophilic than a corresponding residue in the reference NR polypeptide sequence; and (c) mutating the residue in the test NR polypeptide sequence identified in step (b) to a residue having a different hydrophilicity, whereby the solubility of the test NR polypeptide is altered.

By the term “altering” it is meant any change in the solubility of the test NR polypeptide, including preferably a change to make the polypeptide more soluble. Such approaches to obtain soluble proteins for crystallization studies have been successfully demonstrated in the case of HIV integration intergrase and the human leptin cytokine. See Dyda, F., et al., Science (1994) December 23; 266(5193):1981-6; and Zhang et al., Nature (1997) May 8; 387(6629):206-9.

Typically, such a change involves substituting a residue that is more hydrophilic than the wild type residue. Hydrophobicity and hydrophilicity criteria and comparision information are set forth herein below. Optionally, the reference NR polypeptide sequence is an AR or a PR sequence, and the test polypeptide sequence is a GR polypeptide sequence. Alternatively, the reference polypeptide sequence is a crystalline GR LBD. The comparing of step (b) is preferably by sequence alignment. More preferably, the screening is carried out in bacteria, even more preferably, in E coli.

A method for modifying a test NR polypeptide to alter and preferably improve the solubility, stability in solution and other solution behavior, to alter and preferably improve the folding and stability of the folded structure, and to alter and preferably improve the ability to form ordered crystals is also provided in accordance with the present invention. The aforementioned characteristics are representative “desired” or “predetermined characteristics or phenotypes.

In a preferred embodiment, the method comprises:

(a) providing a test NR polypeptide sequence for which the solubility, stability in solution, other solution behavior, tendency to fold properly, ability to form ordered crystals, or combination thereof is different from that desired;

(b) aligning the test NR polypeptide sequence with the sequences of other reference NR polypeptides for which the X-ray structure is available and for which the solution properties, folding behavior and crystallization properties are closer to those desired;

(c) building a three-dimensional model for the test NR polypeptide using the three-dimensional coordinates of the X-ray structure(s) of one or more of the reference polypeptides and their sequence alignment with the test NR polypetide sequence;

(d) optionally, optimizing the side-chain conformations in the three-dimensional model by generating many alternative side-chain conformations, refining by energy minimization, and selecting side-chain conformations with lower energy;

(e) examining the three-dimensional model for the test NR graphically for lipophilic side-chains that are exposed to solvent, for clusters of two or more lipophilic side-chains exposed to solvent, for lipophilic pockets and clefts on the surface of the protein model, and in particular for sites on the surface of the protein model that are more lipophilic than the corresponding sites on the structure(s) of the reference NR polypeptide(s);

(f) for each residue identified in step (e), mutating the amino acid to an amino acid with different hydrophilicity, and usually to a more hydrophilic amino acid, whereby the exposed lipophilic sites are reduced, and the solution properties improved;

(g) examining the three-dimensional model graphically at each site where the amino acid in the test NR polypeptide is different from the amino acid at the corresponding position in the reference NR polypeptide, and checking whether the amino acid in the test NR polypeptide makes favorable interactions with the atoms that lie around it in the three-dimensional model, considering the side-chain conformations predicted in steps (c) and, optionally step (d), as well as likely alternative conformations of the side-chains, and also considering the possible presence of water molecules (for this analysis, an amino acid is considered to make “favorable interactions with the atoms that lie around it” if these interactions are more favorable than the interactions that would be obtained if it was replaced by any of the 19 other naturally-occurring amino acids);

(h) for each residue identified in step (g) as not making favorable interactions with the atoms that lie around it, mutating the residue to another amino acid that could make better interactions with the atoms that lie around it, thereby promoting the tendency for the test NR polypeptide to fold into a stable structure with improved solution properties, less tendency to unfold, and greater tendency to form ordered crystals;

(i) examining the three-dimensional model graphically at each residue position where the amino acid in the test NR polypeptide is different from the amino acid at the corresponding position in the reference NR polypeptide, and checking whether the steric packing, hydrogen bonding and other energetic interactions could be improved by mutating that residue or any one or more of the surrounding residues lying within 8 angstroms in the three-dimensional model;

(j) for each residue position identified in step (i) as potentially allowing an improvement in the packing, hydrogen bonding and energetic interactions, mutating those residues individually or in combination to residues that could improve the packing, hydrogen bonding and energetic interactions, thereby promoting the tendency for the test NR polypeptide to fold into a stable structure with improved solution properties, less tendency to unfold, and greater tendency to form ordered crystals.

By the term “graphically” it is meant through the use of computer aided graphics, such by the use of a software package disclosed herein above. Optionally, in this embodiment, the reference NR polypeptide is AR, or preferably PR, when the test NR polypeptide is GRα. Alternatively, the reference NR polypeptide is GRα, and the test NR polypeptide is GRβ or MR.

An isolated GR polypeptide comprising a mutation in a ligand binding domain, wherein the mutation alters the solubility of the ligand binding domain, is also disclosed. An isolated GR polypeptide, or functional portion thereof, having one or more mutations comprising a substitution of a hydrophobic amino acid residue by a hydrophilic amino acid residue in a ligand binding domain is also disclosed. Preferably, in each case, the mutation can be at a residue selected from the group consisting of V552, W557, F602, L636, Y648, W712, L741, L535, V538, C638, M691, V702, Y648, Y660, L685, M691, V702, W712, L733, Y764 and combinations thereof. More preferably, the mutation is selected from the group consisting of V552K, W557S, F602S, F602D, F602E, F602Y, F602T, F602N, F602C, L636E, Y648Q, W712S, L741 R, L535T, V538S, C638S, M691T, V702T, W712T and combinations thereof. Even more preferably, the mutation is made by targeted point or randomizing mutagenesis. Hydrophobicity and hyrdrophilicity criteria and comparision information are set forth herein below.

As discussed above, the GRα gene can be translated from its mRNA by alternative initiation from an internal ATG codon (Yudt & Cidlowski (2001) Molec. Endocrinol. 15: 1093-1103). This codon codes for methionine at position 27 and translation from this position produces a slightly smaller protein. These two isoforms, translated from the same gene, are referred to as GR-A and GR-B. It has been shown in a cellular system that the shorter GR-B form is more effective in initiating transcription from a GRE compared to GR-A. Additionally, another form of GR, called GRβ is produced by an alternative splicing event. The GRβ protein differs from GRα at the very C-terminus, where the final 50 amino acids are replaced with a 15 amino acid segment. These two isoforms are 100% identical up to amino acid 727. No sequence similarity exists between GRα and GRβ at the C-terminus beyond position 727. GRβ has been shown to be a dominant negative regulator of GRα-mediated gene transcription (Oakley, Sar & Cidlowski (1996) J. Biol. Chem. 271: 9550-9559). It has been suggested that some of the tissue specific effects observed with glucocorticoid treatment may in part be due to the presence of varying amounts of isoform in certain cell-types. This method is also applicable to any other subfamily so organized. Thus, while the amino acid residue numbers referenced above pertain to GR-A, the polypeptides of the present invention also have a mutation at an analogous position in any polypeptide based on a sequence alignment (such as prepared by BLAST or other approach disclosed herein or known in the art) to GRα, which are not forth herein for convenience.

As used in the following discussion, the terms “engineered NR, SR or GR”, “engineered NR, SR or GR LDB”, “NR, SR or GR mutant”, and “NR, SR or GR LBD mutant” refers to polypeptides having amino acid sequences that contain at least one mutation in the wild-type sequence, including at an analogous position in any polypeptide based on a sequence alignment to GRα. The terms also refer to NR, SR or GR and NR, SR or GR LBD polypeptides which are capable of exerting a biological effect in that they comprise all or a part of the amino acid sequence of an engineered mutant polypeptide of the present invention, or cross-react with antibodies raised against an engineered mutant polypeptide, or retain all or some or an enhanced degree of the biological activity of the engineered mutant amino acid sequence or protein. Such biological activity can include the binding of small molecules in general, the binding of glucocorticoids in particular and even more particularly the binding of dexamethasone.

The terms “engineered NR, SR or GR LBD” and “NR, SR or GR LBD mutant” also includes analogs of an engineered NR, SR or GR polypeptide or NR, SR or GR LBD or GR LBD mutant polypeptide. By “analog” is intended that a DNA or polypeptide sequence can contain alterations relative to the sequences disclosed herein, yet retain all or some or an enhanced degree of the biological activity of those sequences. Analogs can be derived from genomic nucleotide sequences or from other organisms, or can be created synthetically. Those of skill in the art will appreciate that other analogs, as yet undisclosed or undiscovered, can be used to design and/or construct mutant analogs. There is no need for an engineered mutant polypeptide to comprise all or substantially all of the amino acid sequence of the wild type polypeptide (e.g. SEQ ID NOs:2 or 10). Shorter or longer sequences are anticipated to be of use in the invention; shorter sequences are herein referred to as “segments”. Thus, the terms “engineered NR, SR or GR LBD” and “NR, SR or GR LBD mutant” also includes fusion, chimeric or recombinant engineered NR, SR or GR LBD or NR, SR or GR LBD mutant polypeptides and proteins comprising sequences of the present invention. Methods of preparing such proteins are disclosed herein above.

X.D. Sequence Similarity and Identity

As used herein, the term “substantially similar” as applied to GR means that a particular sequence varies from nucleic acid sequence of any of odd numbered SEQ ID NOs:1-15, or the amino acid sequence of any of even numbered SEQ ID NOs:2-16 by one or more deletions, substitutions, or additions, the net effect of which is to retain at least some of biological activity of the natural gene, gene product, or sequence. Such sequences include “mutant” or “polymorphic” sequences, or sequences in which the biological activity and/or the physical properties are altered to some degree but retains at least some or an enhanced degree of the original biological activity and/or physical properties. In determining nucleic acid sequences, all subject nucleic acid sequences capable of encoding substantially similar amino acid sequences are considered to be substantially similar to a reference nucleic acid sequence, regardless of differences in codon sequences or substitution of equivalent amino acids to create biologically functional equivalents.

X.D.1. Sequences That are Substantially Identical to an Engineered NR, SR or GR or NR, SR or GR LBD Mutant Sequence of the Present Invention

Nucleic acids that are substantially identical to a nucleic acid sequence of an engineered NR, SR or GR or NR, SR or GR LBD mutant of the present invention, e.g. allelic variants, genetically altered versions of the gene, etc., bind to an engineered NR, SR or GR or NR, SR or GR LBD mutant sequence under stringent hybridization conditions. By using probes, particularly labeled probes of DNA sequences, one can isolate homologous or related genes. The source of homologous genes can be any species, e.g. primate species; rodents, such as rats and mice, canines, felines, bovines, equines, yeast, nematodes, etc.

Between mammalian species, e.g. human and mouse, homologs have substantial sequence similarity, i.e. at least 75% sequence identity between nucleotide sequences. Sequence similarity is calculated based on a reference sequence, which can be a subset of a larger sequence, such as a conserved motif, coding region, flanking region, etc. A reference sequence will usually be at least about 18 nt long, more usually at least about 30 nt long, and can extend to the complete sequence that is being compared. Algorithms for sequence analysis are known in the art, such as BLAST, described in Altschul et al., (1990) J. Mol. Biol. 215: 403-10. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/).

This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold. These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are then extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when the cumulative alignment score falls off by the quantity X from its maximum achieved value, the cumulative score goes to zero or below due to the accumulation of one or more negative-scoring residue alignments, or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength W=11, an expectation E=10, a cutoff of 100, M=5, N=4, and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a wordlength (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix. See Henikoff & Henikoff, (1989) Proc Natl Acad Sci U.S.A. 89: 10915.

In addition to calculating percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences. See, e.g., Karlin and Altschul, (1993) Proc Natl Acad Sci U.S.A. 90: 5873-5887. One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a test nucleic acid sequence is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid sequence to the reference nucleic acid sequence is less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001.

Percent identity or percent similarity of a DNA or peptide sequence can be determined, for example, by comparing sequence information using the GAP computer program, available from the University of Wisconsin Geneticist Computer Group. The GAP program utilizes the alignment method of Needleman et al., (1970) J. Mol. Biol. 48: 443, as revised by Smith et al., (1981) Adv. Appl. Math. 2:482. Briefly, the GAP program defines similarity as the number of aligned symbols (i.e., nucleotides or amino acids) which are similar, divided by the total number of symbols in the shorter of the two sequences. The preferred parameters for the GAP program are the default parameters, which do not impose a penalty for end gaps. See, e.g., Schwartz et al., eds., (1979), Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, pp. 357-358, and Gribskov et al., (1986) Nucl. Acids. Res. 14: 6745.

The term “similarity” is contrasted with the term “identity”. Similarity is defined as above; “identity”, however, means a nucleic acid or amino acid sequence having the same amino acid at the same relative position in a given family member of a gene family. Homology and similarity are generally viewed as broader terms than the term identity. Biochemically similar amino acids, for example leucine/isoleucine or glutamate/aspartate, can be present at the same position—these are not identical per se, but are biochemically “similar.” As disclosed herein, these are referred to as conservative differences or conservative substitutions. This differs from a conservative mutation at the DNA level, which changes the nucleotide sequence without making a change in the encoded amino acid, e.g. TCC to TCA, both of which encode serine.

As used herein, DNA analog sequences are “substantially identical” to specific DNA sequences disclosed herein if: (a) the DNA analog sequence is derived from coding regions of the nucleic acid sequence shown in any one of odd numbered SEQ ID NOs:1-15 or (b) the DNA analog sequence is capable of hybridization with DNA sequences of (a) under stringent conditions and which encode a biologically active GRα or GRα LBD gene product; or (c) the DNA sequences are degenerate as a result of alternative genetic code to the DNA analog sequences defined in (a) and/or (b). Substantially identical analog proteins and nucleic acids will have between about 70% and 80%, preferably between about 81% to about 90% or even more preferably between about 91% and 99% sequence identity with the corresponding sequence of the native protein or nucleic acid. Sequences having lesser degrees of identity but comparable biological activity are considered to be equivalents.

As used herein, “stringent conditions” means conditions of high stringency, for example 6×SSC, 0.2% polyvinylpyrrolidone, 0.2% Ficoll, 0.2% bovine serum albumin, 0.1% sodium dodecyl sulfate, 100 μg/ml salmon sperm DNA and 15% formamide at 68° C. For the purposes of specifying additional conditions of high stringency, preferred conditions are salt concentration of about 200 mM and temperature of about 45° C. One example of such stringent conditions is hybridization at 4×SSC, at 65° C., followed by a washing in 0.1×SSC at 65° C. for one hour. Another exemplary stringent hybridization scheme uses 50% formamide, 4×SSC at 42° C.

In contrast, nucleic acids having sequence similarity are detected by hybridization under lower stringency conditions. Thus, sequence identity can be determined by hybridization under lower stringency conditions, for example, at 50° C. or higher and 0.1×SSC (9 mM NaCl/0.9 mM sodium citrate) and the sequences will remain bound when subjected to washing at 55° C. in 1×SSC.

As used herein, the term “complementary sequences” means nucleic acid sequences that are base-paired according to the standard Watson-Crick complementarity rules. The present invention also encompasses the use of nucleotide segments that are complementary to the sequences of the present invention.

Hybridization can also be used for assessing complementary sequences and/or isolating complementary nucleotide sequences. As discussed above, nucleic acid hybridization will be affected by such conditions as salt concentration, temperature, or organic solvents, in addition to the base composition, length of the complementary strands, and the number of nucleotide base mismatches between the hybridizing nucleic acids, as will be readily appreciated by those skilled in the art. Stringent temperature conditions will generally include temperatures in excess of about 30° C., typically in excess of about 37° C., and preferably in excess of about 45° C. Stringent salt conditions will ordinarily be less than about 1,000. mM, typically less than about 500 mM, and preferably less than about 200 mM. However, the combination of parameters is much more important than the measure of any single parameter. See, e.g., Wetmur & Davidson, (1968) J. Mol. Biol. 31: 349-70. Determining appropriate hybridization conditions to identify and/or isolate sequences containing high levels of homology is well known in the art. See, e.g., Sambrook et al., (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, N.Y.

X.D.2. Functional Equivalents of an Engineered NR, SR or GR or NR, SR, GR LBD Mutant Nucleic Acid Sequence of the Present Invention

As used herein, the term “functionally equivalent codon” is used to refer to codons that encode the same amino acid, such as the ACG and AGU codons for serine. For example, GRα or GRα LBD-encoding nucleic acid sequences comprising any one of odd numbered SEQ ID NOs:1-15, which have functionally equivalent codons are covered by the present invention. Thus, when referring to the sequence example presented in odd numbered SEQ ID NOs:1-15, applicants provide substitution of functionally equivalent codons into the sequence example of in odd numbered SEQ ID NOs:1-15. Thus, applicants are in possession of amino acid and nucleic acids sequences which include such substitutions but which are not set forth herein in their entirety for convenience.

It will also be understood by those of skill in the art that amino acid and nucleic acid sequences can include additional residues, such as additional N- or C-terminal amino acids or 5′ or 3′ nucleic acid sequences, and yet still be essentially as set forth in one of the sequences disclosed herein, so long as the sequence retains biological protein activity where polypeptide expression is concerned. The addition of terminal sequences particularly applies to nucleic acid sequences which can, for example, include various non-coding sequences flanking either of the 5′ or 3′ portions of the coding region or can include various internal sequences, i.e., introns, which are known to occur within genes.

X.D.3. Biological Equivalents

The present invention envisions and includes biological equivalents of a engineered NR, SR or GR or NR, SR or GR LBD mutant polypeptide of the present invention. The term “biological equivalent” refers to proteins having amino acid sequences which are substantially identical to the amino acid sequence of an engineered NR, SR or GR LBD mutant of the present invention and which are capable of exerting a biological effect in that they are capable of binding small molecules or cross-reacting with anti- NR, SR or GR or NR, SR or GR LBD mutant antibodies raised against an engineered mutant NR, SR or GR or NR, SR or GR LBD polypeptide of the present invention.

For example, certain amino acids can be substituted for other amino acids in a protein structure without appreciable loss of interactive capacity with, for example, structures in the nucleus of a cell. Since it is the interactive capacity and nature of a protein that defines that protein's biological functional activity, certain amino acid sequence substitutions can be made in a protein sequence (or the nucleic acid sequence encoding it) to obtain a protein with the same, enhanced, or antagonistic properties. Such properties can be achieved by interaction with the normal targets of the protein, but this need not be the case, and the biological activity of the invention is not limited to a particular mechanism of action. It is thus in accordance with the present invention that various changes can be made in the amino acid sequence of an engineered NR, SR or GR or NR, SR or GR LBD mutant polypeptide of the present invention or its underlying nucleic acid sequence without appreciable loss of biological utility or activity.

Biologically equivalent polypeptides, as used herein, are polypeptides in which certain, but not most or all, of the amino acids can be substituted. Thus, when referring to the sequence examples presented in any of even numbered SEQ ID NOs:2-16, applicants envision substitution of codons that encode biologically equivalent amino acids, as described herein, into a sequence example of even numbered SEQ ID NOs: 2-16, respectively. Thus, applicants are in possession of amino acid and nucleic acids sequences which include such substitutions but which are not set forth herein in their entirety for convenience.

Alternatively, functionally equivalent proteins or peptides can be created via the application of recombinant DNA technology, in which changes in the protein structure can be engineered, based on considerations of the properties of the amino acids being exchanged, e.g. substitution of Ile for Leu. Changes designed by man can be introduced through the application of site-directed mutagenesis techniques, e.g., to introduce improvements to the antigenicity of the protein or to test an engineered mutant polypeptide of the present invention in order to modulate lipid-binding or other activity, at the molecular level.

Amino acid substitutions, such as those which might be employed in modifying an engineered mutant polypeptide of the present invention are generally, but not necessarily, based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. An analysis of the size, shape and type of the amino acid side-chain substituents reveals that arginine, lysine and histidine are all positively charged residues; that alanine, glycine and serine are all of similar size; and that phenylalanine, tryptophan and tyrosine all have a generally similar shape. Therefore, based upon these considerations, arginine, lysine and histidine; alanine, glycine and serine; and phenylalanine, tryptophan and tyrosine; are defined herein as biologically functional equivalents. Those of skill in the art will appreciate other biologically functionally equivalent changes. It is implicit in the above discussion, however, that one of skill in the art can appreciate that a radical, rather than a conservative substitution is warranted in a given situation. Non-conservative substitutions in engineered mutant LBD polypeptides of the present invention are also an aspect of the present invention.

In making biologically functional equivalent amino acid substitutions, the hydropathic index of amino acids can be considered. Each amino acid has been assigned a hydropathic index on the basis of their hydrophobicity and charge characteristics, these are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine (+2.5); methionine (+1.9); alanine (+1.8); glycine (−0.4); threonine (−0.7); serine (−0.8); tryptophan (−0.9); tyrosine (−1.3); proline (−1.6); histidine (−3.2); glutamate (−3.5); glutamine (−3.5); aspartate (−3.5); asparagine (−3.5); lysine (−3.9); and arginine (−4.5).

The importance of the hydropathic amino acid index in conferring interactive biological function on a protein is generally understood in the art (Kyte & Doolittle, (1982), J. Mol. Biol. 157: 105-132, incorporated herein by reference). It is known that certain amino acids can be substituted for other amino acids having a similar hydropathic index or score and still retain a similar biological activity. In making changes based upon the hydropathic index, the substitution of amino acids whose hydropathic indices are within ±2 of the original value is preferred, those which are within ±1 of the original value are particularly preferred, and those within ±0.5 of the original value are even more particularly preferred.

It is also understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity. U.S. Pat. No. 4,554,101, incorporated herein by reference, states that the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with its immunogenicity and antigenicity, i.e. with a biological property of the protein. It is understood that an amino acid can be substituted for another having a similar hydrophilicity value and still obtain a biologically equivalent protein.

As detailed in U.S. Pat. No. 4,554,101, the following hydrophilicity values have been assigned to amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0±1); glutamate (+3.0±1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (−0.4); proline (−0.5±1); alanine (−0.5); histidine (−0.5); cysteine (−1.0); methionine (−1.3); valine (−1.5); leucine (−1.8); isoleucine (−1.8); tyrosine (−2.3); phenylalanine (−2.5); tryptophan (−3.4).

In making changes based upon similar hydrophilicity values, the substitution of amino acids whose hydrophilicity values are within ±2 of the original value is preferred, those which are within ±1 of the original value are particularly preferred, and those within ±0.5 of the original value are even more particularly preferred.

While discussion has focused on functionally equivalent polypeptides arising from amino acid changes, it will be appreciated that these changes can be effected by alteration of the encoding DNA, taking into consideration also that the genetic code is degenerate and that two or more codons can code for the same amino acid.

Thus, it will also be understood that this invention is not limited to the particular amino acid and nucleic acid sequences of any of SEQ ID NOs:1-16. Recombinant vectors and isolated DNA segments can therefore variously include an engineered NR, SR or GR or NR, SR or GR LBD mutant polypeptide-encoding region itself, include coding regions bearing selected alterations or modifications in the basic coding region, or include larger polypeptides which nevertheless comprise an NR, SR or GR or NR, SR or GR LBD mutant polypeptide-encoding regions or can encode biologically functional equivalent proteins or polypeptides which have variant amino acid sequences. Biological activity of an engineered NR, SR or GR or NR, SR or GR LBD mutant polypeptide can be determined, for example, by transcription assays known to those of skill in the art.

The nucleic acid segments of the present invention, regardless of the length of the coding sequence itself, can be combined with other DNA sequences, such as promoters, enhancers, polyadenylation signals, additional restriction enzyme sites, multiple cloning sites, other coding segments, and the like, such that their overall length can vary considerably. It is therefore contemplated that a nucleic acid fragment of almost any length can be employed, with the total length preferably being limited by the ease of preparation and use in the intended recombinant DNA protocol. For example, nucleic acid fragments can be prepared which include a short stretch complementary to a nucleic acid sequence set forth in any of odd numbered SEQ ID NOs:1-15, such as about 10 nucleotides, and which are up to 10,000 or 5,000 base pairs in length. DNA segments with total lengths of about 4,000, 3,000, 2,000, 1,000, 500, 200, 100, and about 50 base pairs in length are also useful.

The DNA segments of the present invention encompass biologically functional equivalents of engineered NR, SR or GR, or NR, SR or GR LBD mutant polypeptides. Such sequences can rise as a consequence of codon redundancy and functional equivalency that are known to occur naturally within nucleic acid sequences and the proteins thus encoded. Alternatively, functionally equivalent proteins or polypeptides can be created via the application of recombinant DNA technology, in which changes in the protein structure can be engineered, based on considerations of the properties of the amino acids being exchanged. Changes can be introduced through the application of site-directed mutagenesis techniques, e.g., to introduce improvements to the antigenicity of the protein or to test variants of an engineered mutant of the present invention in order to examine the degree of binding activity, or other activity at the molecular level. Various site-directed mutagenesis techniques are known to those of skill in the art and can be employed in the present invention.

The invention further encompasses fusion proteins and peptides wherein an engineered mutant coding region of the present invention is aligned within the same expression unit with other proteins or peptides having desired functions, such as for purification or immunodetection purposes.

Recombinant vectors form important further aspects of the present invention. Particularly useful vectors are those in which the coding portion of the DNA segment is positioned under the control of a promoter. The promoter can be that naturally associated with an NR, SR or GR gene, as can be obtained by isolating the 5′ non-coding sequences located upstream of the coding segment or exon, for example, using recombinant cloning and/or PCR technology and/or other methods known in the art, in conjunction with the compositions disclosed herein.

In other embodiments, certain advantages will be gained by positioning the coding DNA segment under the control of a recombinant, or heterologous, promoter. As used herein, a recombinant or heterologous promoter is a promoter that is not normally associated with an NR, SR or GR gene in its natural environment. Such promoters can include promoters isolated from bacterial, viral, eukaryotic, or mammalian cells. Naturally, it will be important to employ a promoter that effectively directs the expression of the DNA segment in the cell type chosen for expression. The use of promoter and cell type combinations for protein expression is generally known to those of skill in the art of molecular biology (See, e.g., Sambrook et al., (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York, specifically incorporated herein by reference). The promoters employed can be constitutive or inducible and can be used under the appropriate conditions to direct high level expression of the introduced DNA segment, such as is advantageous in the large-scale production of recombinant proteins or peptides. One preferred promoter system contemplated for use in high-level expression is a T7 promoter-based system.

X.E. Antibodies to an Engineered NR, SR or GR or NR, SR, GR LBD Mutant Polypeptide of the Present Invention

The present invention also provides an antibody that specifically binds a engineered NR, SR or GR or NR, SR, GR LBD mutant polypeptide and methods to generate same. The term “antibody” indicates an immunoglobulin protein, or functional portion thereof, including a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a single chain antibody, Fab fragments, and a Fab expression library. “Functional portion” refers to the part of the protein that binds a molecule of interest. In a preferred embodiment, an antibody of the invention is a monoclonal antibody. Techniques for preparing and characterizing antibodies are well known in the art (See, e.g., Harlow & Lane (1988) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.). A monoclonal antibody of the present invention can be readily prepared through use of well-known techniques such as the hybridoma techniques exemplified in U.S. Pat. No 4,196,265 and the phage-displayed techniques disclosed in U.S. Pat. No. 5,260,203.

The phrase “specifically (or selectively) binds to an antibody”, or “specifically (or selectively) immunoreactive with”, when referring to a protein or peptide, refers to a binding reaction which is determinative of the presence of the protein in a heterogeneous population of proteins and other biological materials. Thus, under designated immunoassay conditions, the specified antibodies bind to a particular protein and do not show significant binding to other proteins present in the sample. Specific binding to an antibody under such conditions can require an antibody that is selected for its specificity for a particular protein. For example, antibodies raised to a protein with an amino acid sequence encoded by any of the nucleic acid sequences of the invention can be selected to obtain antibodies specifically immunoreactive with that protein and not with unrelated proteins.

The use of a molecular cloning approach to generate antibodies, particularly monoclonal antibodies, and more particularly single chain monoclonal antibodies, are also provided. The production of single chain antibodies has been described in the art. See, e.g., U.S. Pat. No. 5,260,203. For this approach, combinatorial immunoglobulin phagemid libraries are prepared from RNA isolated from the spleen of the immunized animal, and phagemids expressing appropriate antibodies are selected by panning on endothelial tissue. The advantages of this approach over conventional hybridoma techniques are that approximately 10⁴ times as many antibodies can be produced and screened in a single round, and that new specificities are generated by heavy (H) and light (L) chain combinations in a single chain, which further increases the chance of finding appropriate antibodies. Thus, an antibody of the present invention, or a “derivative” of an antibody of the present invention, pertains to a single polypeptide chain binding molecule which has binding specificity and affinity substantially similar to the binding specificity and affinity of the light and heavy chain aggregate variable region of an antibody described herein.

The term “immunochemical reaction”, as used herein, refers to any of a variety of immunoassay formats used to detect antibodies specifically bound to a particular protein, including but not limited to competitive and non-competitive assay systems using techniques such as radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, immunoradiometric assays, gel diffusion precipitation reactions, immunodiffusion assays, in situ immunoassays (e.g., using colloidal gold, enzyme or radioisotope labels), western blots, precipitation reactions, agglutination assays (e.g., gel agglutination assays, hemagglutination assays), complement fixation assays, immunofluorescence assays, protein A assays, and immunoelectrophoresis assays, etc. See Harlow & Lane (1988) for a description of immunoassay formats and conditions.

X.F. Method for Detecting an Engineered NR, SR or GR or NR, SR, GR LBD Mutant Polypeptide or an Nucleic Acid Molecule Encoding the Same

In another aspect of the invention, a method is provided for detecting a level of an engineered NR, SR or GR or NR, SR, GR LBD mutant polypeptide using an antibody that specifically recognizes an engineered NR, SR or GR or NR, SR, GR LBD mutant polypeptide, or portion thereof. In a preferred embodiment, biological samples from an experimental subject and a control subject are obtained, and an engineered NR, SR or GR or NR, SR, GR LBD mutant polypeptide is detected in each sample by immunochemical reaction with the antibody. More preferably, the antibody recognizes amino acids of any one of the even-numbered SEQ ID NOs:4, 6, 8, 12, 14, and 16, and is prepared according to a method of the present invention for producing such an antibody.

In one embodiment, an antibody is used to screen a biological sample for the presence of an engineered NR, SR or GR or NR, SR, GR LBD mutant polypeptide. A biological sample to be screened can be a biological fluid such as extracellular or intracellular fluid, or a cell or tissue extract or homogenate. A biological sample can also be an isolated cell (e.g., in culture) or a collection of cells such as in a tissue sample or histology sample. A tissue sample can be suspended in a liquid medium or fixed onto a solid support such as a microscope slide. In accordance with a screening assay method, a biological sample is exposed to an antibody immunoreactive with an engineered NR, SR or GR or NR, SR, GR LBD mutant polypeptide whose presence is being assayed, and the formation of antibody-polypeptide complexes is detected. Techniques for detecting such antibody-antigen conjugates or complexes are well known in the art and include but are not limited to centrifugation, affinity chromatography and the like, and binding of a labeled secondary antibody to the antibody-candidate receptor complex.

In another aspect of the invention, a method is provided for detecting a nucleic acid molecule that encodes an engineered NR, SR or GR or NR, SR, GR LBD mutant polypeptide. According to the method, a biological sample having nucleic acid material is procured and hybridized under stringent hybridization conditions to an engineered NR, SR or GR or NR, SR, GR LBD mutant polypeptide-encoding nucleic acid molecule of the present invention. Such hybridization enables a nucleic acid molecule of the biological sample and an engineered NR, SR or GR or NR, SR, GR LBD mutant polypeptide encoding-nucleic acid molecule to form a detectable duplex structure. Preferably, the an engineered NR, SR or GR or NR, SR, GR LBD mutant polypeptide encoding-nucleic acid molecule includes some or all nucleotides of any one of the odd-numbered SEQ ID NOs:3, 5, 7, 11, 13, and 15. Also preferably, the biological sample comprises human nucleic acid material.

XI. The Role of the Three-Dimensional Structure of the GRα LDB in Solving Additional NR, SR or GR Crystals

Because polypeptides can crystallize in more than one crystal form, the structural coordinates of a GRα LBD, or portions thereof, as provided by the present invention, are particularly useful in solving the structure of other crystal forms of GRα and the crystalline forms of other NRs, SRs and GRs. The coordinates provided in the present invention can also be used to solve the structure of NR, SR or GR and NR, SR or GR LBD mutants (such as those described in Sections IX and X above), NR, SR or GR LDB co-complexes, or of the crystalline form of any other protein with significant amino acid sequence homology to any functional domain of NR, SR or GR.

XI.A. Determining the Three-Dimensional Structure of a Polypeptide Using the Three-Dimensional Structure of the GRα LBD as a Template in Molecular Replacement

One method that can be employed for the purpose of solving additional GR crystal structures is molecular replacement. See generally, Rossmann, ed, (1972) The Molecular Replacement Method, Gordon & Breach, New York. In the molecular replacement method, the unknown crystal structure, whether it is another crystal form of a GRα or a GRα LBD, (i.e. a GRα or a GRα LBD mutant), or an NR, SR or GR or an NR, SR or GR LBD polypeptide complexed with another compound (a “co-complex”), or the crystal of some other protein with significant amino acid sequence homology to any functional region of the GRα LBD, can be determined using the GRα LBD structure coordinates provided in Table 4. This method provides an accurate structural form for the unknown crystal more quickly and efficiently than attempting to determine such information ab initio.

In addition, in accordance with this invention, NR, SR or GR and NR, SR or GR LBD mutants can be crystallized in complex with known modulators. The crystal structures of a series of such complexes can then be solved by molecular replacement and compared with that of the wild-type NR, SR or GR or the wild-type NR, SR or GR LBD. Potential sites for modification within the various binding sites of the enzyme can thus be identified. This information provides an additional tool for determining the most efficient binding interactions, for example, increased hydrophobic interactions, between the GRα LBD and a chemical entity or compound.

All of the complexes referred to in the present disclosure can be studied using X-ray diffraction techniques (See, e.g., Blundell & Johnson (1985) Method. Enzymol., 114A & 115B, (Wyckoff et al., eds.), Academic Press; McRee, (1993) Practical Protein Crystallography, Academic Press, New York) and can be refined using computer software, such as the X-PLOR™ program (Brünger, (1992) X-PLOR, Version 3.1. A System for X-ray Crystallography and NMR, Yale University Press, New Haven, Conn.; X-PLOR is available from Molecular Simulations, Inc., San Diego, Calif.) and the XTAL-VIEW program (McRee, (1992) J. Mol. Graphics 10: 44-46; McRee, (1993) Practical Protein Crystallography, Academic Press, San Diego, Calif.). This information can thus be used to optimize known classes of GR and GR LBD modulators, and more importantly, to design and synthesize novel classes of GR and GR LBD modulators.

LABORATORY EXAMPLES

The following Laboratory Examples have been included to illustrate preferred modes of the invention. Certain aspects of the following Laboratory Examples are described in terms of techniques and procedures found or contemplated by the present inventors to work well in the practice of the invention. These Laboratory Examples are exemplified through the use of standard laboratory practices of the inventors. In light of the present disclosure and the general level of skill in the art, those of skill will appreciate that the following Laboratory Examples are intended to be exemplary only and that numerous changes, modifications and alterations can be employed without departing from the spirit and scope of the invention.

Example 1 Construction of the Modified pET24 Expression Vector

The expression vector pGEX-2T (Amersham Pharmacia Biotech, Piscataway, N.J.) was used as a template in a polymerase chain reaction to engineer a polyhistidine tag in frame to the sequence encoding glutathione S-transferase (GST) and a thrombin protease site. The forward primer contained a Nde I site (5′ CGG CGG CGC CAT ATG AAA AAA GGT (CAT )₆ GGT TCC CCT ATA CTA GGT TAT TGG A 3′) (SEQ ID NO:19) and the reverse primer (5′ CGG CGG CGC GGA TCC ACG CGG MC CAG ATC CGA 3′) (SEQ ID NO:20) contained a BamH I site which allowed for direct cloning of the amplfied product into pET24a (Novagen, Inc., Madison, Wis.) following restiction enzyme digestion. The resulting sequence of the modified GST (SEQ ID NO:21) (last six residues are thrombin protease site) is below: MKKGHHHHHH HGSPILGYWK IKGLVQPTRL LLEYLEEKYE EHLYERDEGD 50 KWRNKKFELG LEFPNLPYYI DGDVKLTQSM AIIRYIADKH NMLGGCPKER 100 AEISMLEGAV LDIRYGVSRI AYSKDFETLK VDFLSKLPEM LKMFEDRLCH 150 KTYLNGDHVT HPDFMLYDAL DVVLYMDPMC LDAFPKLVCF KKRIEAIPQI 200 DKYLKSSKYI AWPLQGWQAT FGGGDHPPKS DLVPRGS 237

Example 2 Mutagenesis (F602S AND F602D) of Human GR Ligand Binding Domain (LBD)

Two complimentary oligonucleotides for each desired mutation were constructed. The following sequences represent the oligonucleotides for the Phenylalanine 602 Serine mutation: (SEQ ID NO:22) Forward Primer (F602S): 5′ TAC TCC TGG ATG TCC CTT ATG GCA TTT GCT CT 3′ (SEQ ID NO:23) Reverse Primer (F602S): 5′ AG AGC AAA TGC CAT AAG GGA CAT CCA GGA GTA 3′

Another separate mutation was also constructed. The sequences below represent the oligonucleotides for the Phenylalanine 602 Aspartic Acid mutation: (SEQ ID NO:24) Forward Primer (F602D): 5′ TAC TCC TGG ATG GAC CTT ATG GCA TTT GCT CT 3′ (SEQ ID NO:25) Reverse Primer (F602D): 5′ AG AGC AAA TGC CAT AAG GTC CAT CCA GGA GTA 3′

The underlined letters depict the base changes from the wild type human GR sequence. The GR LBD (amino acids 521-777) (SEQ ID NOs:9-10) previously cloned into the pRSET A vector (Invitrogen of Carlsbad, Calif.) was used as the backbone to create the mutants. The procedure used to make the mutation is outlined in the QuickChange Site-Directed Mutagenesis Kit sold by Stratagene, La Jolla, Calif. (Catalog #200518). After the constructs were sequence verified, the mutants of GR-LBD were subcloned inframe with the glutathione S-transferase in the modified pET24 expression vector. A thrombin protease site at the C-terminus of the glutathione S-transferase allows for cleavage of the resultant fusion protein following expression.

The resulting final amino acid sequences for the mutant GR LBDs are below. The underlined, bolded amino acids depict the changes from the wild type human GR sequence. GR-LBD(521-777) F602S VPATLPQLTP TLVSLLEVIE PEVLYAGYDS SVPDSTWRIM TTLNMLGGRQ (SEQ ID NO:12) VIAAVKWAKA IPGFRNLHLD DQMTLLQYSW M S LMAFALGW RSYRQSSANL LCFAPDLIIN EQRMTLPCMY DQCKHMLYVS SELHRLQVSY EEYLCMKTLL LLSSVPKDGL KSQELFDEIR MTYIKELGKA IVKREGNSSQ NWQRFYQLTK LLDSMHEVVE NLLNYCFQTF LDKTMSIEFP EMLAEIITNQ IPKYSNGNIK KLLFHQK GR-LBD(521-777) F602D VPATLPQLTP TLVSLLEVIE PEVLYAGYDS SVPDSTWRIM TTLNMLGGRQ (SEQ ID NO:14) VIAAVKWAKA IPGFRNLHLD DQMTLLQYSW M D LMAFALGW RSYRQSSANL LCFAPDLIIN EQRMTLPCMY DQCKHMLYVS SELHRLQVSY EEYLCMKTLL LLSSVPKDGL KSQELFDEIR MTYIKELGKA IVKREGNSSQ NWQRFYQLTK LLDSMHEVVE NLLNYCFQTF LDKTMSIEFP EMLAEIITNQ IPKYSNGNIK KLLFHQK

Example 3 Expression of the Fusion Protein

BL21(DE3) cells (Novagen, Inc., Madison, Wis.) were transformed following established protocols. Following overnight incubation at 37° C. a single colony was used to inoculate a 10 ml LB culture containing 50 μg/ml kanamycin (Sigma Chemical Company, St. Louis, Mo.). The culture was grown for ˜12 hrs at 37° C. and then a 500 μl aliquot was used to inoculate flasks containing 1 liter Circle Grow media (Biol01, Inc., now Qbiogene of Carlsbad, Calif.) and the required antibiotic. The cells were then grown at 22° C. to an OD600 between 1 and 2 and then cooled to 16° C. Following a 30 min equilibration at that temperature, dexamethasone (Spectrum, Gardena, Calif.) (10 μM final concentration) was added. Induction of expression was achieved by adding IPTG (BACHEM AG, Switzerland) (final concentration 1 mM) to the cultures. Expression at 16° C. was continued for ˜24 hrs. Cells were then harvested and frozen at −80° C.

Referring now to FIG. 1A, E. coli expression of mutant 6xHisGST-GR(521-777) F602S is shown. Shown are the pellet (P—insoluble) and eluent (E—soluble Ni++ binding) fractions of protein expressed in the absence of ligand (NL—lanes 2 and 3) or in the presence (10 micromolar) of dexamethasone (DEX), lanes 4 and 5, or RU486, lanes 6 and 7. The positions of molecular mass (kDa) markers M (lane 1) (94, 67, 43, 30, 20 and 14 kDa, respectively) and of the expressed protein are indicated to the left and right sides of the panel, respectively.

Referring now to FIG. 1B, E coli expression of mutant 6xHisGST-GR(521-777) F602D is shown. Shown are eluent fractions from Ni++ chelated resin of two separate samples. Protein was expressed in either the presence (+, lanes 2 and 4, 10 micromolar) or absence (−, lanes 3 and 5) of dexamethasone. The positions of molecular mass (kDa) markers M (lane 1) (94, 67, 43, 30, 20 and 14 kDa, respectively) and of the expressed protein are indicated to the left and right sides of the panel, respectively.

Example 4 Purification Of GR-LBD (F602S)

˜200 g cells were resuspended in 700 mL lysis buffer (50 mM Tris pH=8.0, 150 mM NaCl, 2M Urea, 10% glycerol and 100 μM dexamethasone) and lysed by passing 3 times through an APV Lab 2000 homogenizer. The lysate was subjected to centrifugation (45 minutes, 20,000 g, 4° C.), followed by a second 20 min spin at 20,000 g, 4°. The cleared supernatant was filtered through coarse pre-filters and 50 mM Tris, pH=8.0, containing 150 mM NaCl, 10% glycerol and 1M imidazole was added to obtain a final imidazole concentration of 50 mM. This lysate was loaded onto a XK-26 column (Pharmacia, Peapack, N.J.) packed with SEPHAROSE® [Ni⁺⁺ charged] Chelation resin (Pharmacia, Peapack, N.J.) and pre-equilibrated with lysis buffer supplemented with 50 mM imidazole. Following loading, the column was washed to baseline absorbance with equilibration buffer and a linear urea gradient (2M to 0). For elution the column was developed with a linear gradient from 50 to 500 mM Imidazole in 50 mM Tris pH=8.0, 150 mM NaCl, 10% glycerol and 30 μM dexamethasone. Column fractions of interest were pooled and 500 units of thrombin protease (Amersham Pharmacia Biotech, Piscataway, N.J.) were added for the cleavage of the fusion protein.

This solution was then dialyzed against 1 liter of 50 mM Tris pH=8.0, 150 mM NaCl, 10% glycerol and 20 μM dexamethasone for ˜10 hrs at 4° C. The digested protein sample was filtered and then reloaded onto the same re-equilibrated column. The cleaved GR-LBD was collected in the flow through fraction. The diluted protein sample was concentrated with Centri-prep™ 10K centrifugal filtration devices (Amicon/Millpore, Bedford, Mass.) to a volume of 30 mls and then diluted 5 fold with 50 mM Tris pH=8.0, 10% glycerol, 10 mM DTT, 0.5 mM EDTA and 30 μM dexamethasone. The sample was then loaded onto a pre-equilibrated XK-26 column (Pharmacia, Peapack, N.J.) packed with Poros HQ resin (PerSeptive Biosystems, Framingham, Mass.). The cleaved GR LBD was collected in the flowthrough. The NaCl concentration was adjusted to 500 mM and the dexamethasone concentration was adjusted to 50 μM before the purified protein was concentrated to ˜1 mg/ml using the Centri-prep™ 10K centrifugal filtration devices.

FIG. 1A depicts purification of E. coli expressed GR(521-777) F602S by SDS-PAGE. Lane 1 contains the insoluble pellet fraction. Lane 2 contains the soluble supernatant fraction. Lane 3 contains pooled eluent from intial Ni⁺⁺ column. Lane 4 contains the sample after thrombin digestion. Lane 5 contains the flow through fraction after reload of the Ni⁺⁺ column. Lane 6 contains the concentrated protein after anion exchange. The positions of molecular mass (kDa) markers (in Lane M, 94, 67, 43, 30, 20 and 14 kDa, respectively) and of the expressed protein are indicated to the left and right sides of the panel, respectively. Purfication provides for the removal of any remaining associated bacterial HSPs.

The final resultant sequence (SEQ ID NO:32) of the purified protein is below. The first two residues (underlined and bolded) are vector derived and represent the remaining residues of the thrombin cleavage site following digestion. GS VPATLPQL TPTLVSLLEV IEPEVLYAGY DSSVPDSTWR IMTTLNMLGG RQVIAAVKWA KAIPGFRNLH LDDQMTLLQY SWMSLMAFAL GWRSYRQSSA NLLCFAPDLI INEQRMTLPC MYDQCKHMLY VSSELHRLQV SYEEYLCMKT LLLLSSVPKD GLKSQELFDE IRMTYIKELG KAIVKREGNS SQNWQRFYQL TKLLDSMHEV VENLLNYCFQ TFLDKTMSIE FPEMLAEIIT NQIPKYSNGN IKKLLFHQK

Example 5 Ligand and Coactivator Binding Of GR

All experiments were conducted with buffer containing 10 mM HEPES pH 7.4, 0.15 M NaCl, 3 mM EDTA, 0.005% polysorbate-20 and 5 mM DTT. For activity determinations, 10 nM of fluorescein dexamethasone (Molecular Probes, Eugene, Ore.) was titrated with increasing concentrations of the glucocorticoid receptor in black 96-well plates (CoStar, Cambridge, Mass.). The fluorescence polarization values for each concentration of receptor were determined using a BMG PolarStar Galaxy fluorescence plate reader (BMG Labtechnologies GmbH, Offenburg, Germany) with 485 nm excitation and 520 nm emission filters. Binding isotherms were constructed and apparent EC50 values were determined by non-linear least squares fit of the data to an equation for a simple 1:1 interaction. Note that these EC50 values are not corrected for the unlabeled dexamethasone present in the GR receptor preparations. For stability studies, the fluorescent polarization of 10 nM fluorescein dexamethasone with 1 μM GST-GR LBD 521-777 (F602S) is read at specific time intervals in the presence or absence of 25 uM of a peptide derived from the coactivator TIF2. (SEQ ID NO:17) (TIF2 732-756: QEPVSPKKKENALLRYLLDKDDTKD).

Data from these experiments are presented graphically in FIGS. 2A-2C. These studies demonstrate that the GST-GR fusion protein and the cleaved GR LBD alone bind dexamethasone in a saturable and competable manner (FIG. 2A). It was also found that the GST-GR fusion protein binds a peptide from the coactivator TIF2 with a submicromolar affinity. Binding of the GST-GR fusion protein is enhanced by the agonist dexamethasone (DEX) and inhibited by the antagonist RU486 (FIG. 2B). Finally, it was also found that the addition of the TIF2 peptide stabilizes the dexamethasone binding activity of the GST-GR fusion protein.

FIG. 2B was generated using Biacore techniques. Biacore relies on changes in the refractive index at the surface layer upon binding of a ligand to a protein immobilized on the layer. In this system, a collection of small ligands is injected sequentially in a 2-5 microliter cell, wherein the protein is immobilized within the cell. Binding is detected by surface plasmon resonance (SPR) by recording laser light refracting from the surface. In general, the refractive index change for a given change of mass concentration at the surface layer is practically the same for all proteins and peptides, allowing a single method to be applicable for any protein (Liedberg et al. (1983) Sensors Actuators 4:299-304; Malmquist (1993) Nature 361:186-187). The purified protein is then used in the assay without further preparation. A synthetic peptide with an amino-terminal biotin is coupled to a sensor chip immobilized with streptavidin. The chip thus prepared is then exposed to the potential ligand via the delivery system incorporated in the instruments sold by Biacore (Uppsala, Sweden) to pipet the ligands in a sequential manner (autosampler). The SPR signal on the chip is recorded and changes in the refractive index indicate an interaction between the immobilized target and the ligand. Analysis of the signal kinetics of on rate and off rate allows the discrimination between non-specific and specific interaction.

Example 6 Preparation of the GR/TIF2/Dex Complex

The GR/TIF2/Dex complex was prepared by adding a 2-fold excess of a TIF2 peptide containing sequence of QEPVSPKKKENALLRYLLDKDDTKD (SEQ ID NO:17). The above complex was diluted 10 folds with a buffer containing 500 mM ammonium acetate (NH₄OAC), 50 mM Tris, pH 8.0, 10% glycerol, 10 mM dithiothreitol (DTT), 0.5 mM EDTA, and 0.05% beta-N-octoglucoside (b-OG), and was slowly concentrated to 6.3 mg/ml, then aliquoted and stored at −80° C.

Example 7 Crystallization and Data Collection

The GR/TIF2/DEX crystals were grown at room temperature in hanging drops containing 3.0 ul of the above protein-ligand solutions, and 0.5 ul of well buffer (50 mM HEPES, pH 7.5-8.5 (preferred pH range is 8.0 to 8.5), and 1.7-2.3M ammonium formate). Crystals were also obtained with mixing of the above protein solution and the well buffer at various volume ratios. Crystals appeared overnight and continously grew to a size up to 300 micron within a week. Before data collection, crystals were transiently mixed with the well buffer that contained an additional 25% glycerol, and were then flash frozen in liquid nitrogen.

The GR/TIF2/DEX crystals formed in the P6₁ space group, with a=b=126.014 Å, c=86.312 Å, α=β=900, and γ=120°. Each asymmetry unit contains two molecules of the GR LBD with 56% of solvent content. Data were collected with a Rigaku Raxis IV detector in house. The observed reflections were reduced, merged and scaled with DENZO and SCALEPACK in the HKL2000 package (Z. Otwinowski and W. Minor (1997)).

Example 8 Structure Determination and Refinement

Table 5 is a table of the atomic structure coordinates used as the initial model to solve the structure of the GR/TIF2/dexamethasone complex by molecular replacement. The GR model is a homology model built on the published structure of the progesterone receptor LBD and the SRC1 coactivator peptide from the PPARα/Compound 1/SRC1 structure.

Compound 1 is an agonist of hPPARα, and has the IUPAC name 2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethylphenyl] thiazol-5-yl-carbonyl) amino] methyl} phenoxy] propionic acid.

The initial model for the molecular replacement calculation comprised coordinates for residues 527-776 of wild-type GR together with coordinates for residues 685-697 of SRC-1, a coactivator very similar to TIF2. The model for GR was built from the crystal struture of PR bound to progesterone (Shawn P. Williams and Paul B. Sigler, Nature 393, 392-396 (1998)) using the MVP program (Lambert, 1997). The coordinates for SRC-1 were obtained from a crystal structure of PPARα bound to SRC-1. The SRC-1 model was positioned in the coactivator binding site of GR by rotating the GR model and PPARα/SRC-1 complex into a common orientation that superimposed their backbone atoms.

It is noted that the amino acid sequence for SRC-1 differs substantially from that of TIF2, although both coactivator sequences have the LXXLL motif. Model building, including conversion of side-chains from the SRC-1 and wild-type GR sequences to the actual TIF2 and GR F602S sequences, respectively, was carried out with QUANTA™.

This model was used in molecular replacement search with the CCP4 AmoRe™ program (Collaborative Computational Project Number 4, 1994, “The CCP4 Suite: Programs for Protein Crystallography”, Acta Cryst. D50, 760-763; J. Navaza, Acta Cryst. A50, 157-163 (1994)) to determine the initial structure solutions. Two solutions were obtained from the molecular replacement search with a correlation coefficiency of 43% and an R-factor of 45.3%, consistent with two complexes within each asymmetry unit. The calculated phase from the molecular replacement solutions was improved with solvent flattening, histogram matching and the two-fold noncrystallographic averaging as implement in the CCP4 dm program, and produced a clear map for the GR LBD, the TIF2 peptide and the dexamethasone. As noted above, model building proceeded with QUANTA™, and refinement progressed with CNX (Accelrys, Princeton, N.J.) and multiple cycle of manual rebuilding. The statistics of the structure are summarized in Table 3 and coordinates are presented in FIG. 4.

Surface areas calculated with the Connolly MS program (Michael L. Connolly, “Solvent-Accessible Surfaces of Proteins and Nucleic Acids,” Science 221, 709-713 (1983)) and the MVP program (Lambert, 1997). The pocket volume and binding site accessible waters were calculated with MVP.

Example 9 Random Mutant Library of GR LBD and Selection using the Lacl Fusion System

The expression vector pJS142 Å (Affymax Inc., Palo Alto, Calif.) containing the Lacl protein was used to clone the wild type GR LBD in frame with the Lacl gene. Using standard error-incorporating PCR techniques, a random mutant library was created within the context of the GR LBD. An advantage of the Lacl expression system is that the protein expressed has the ability to bind the plasmid DNA from which it was derived. The mutant fusion proteins produced by the random library were expressed in E. Coli at 37° C. Lysis of the cell cultures was achieved using lysozyme. The cell lysates were then added to a microtiter plate containing the immobilized coactivator peptide biotinylated-TIF2 NR BoxIII. The plasmid DNA was eluted from the DNA-protein complex bound to the plate using 1mM IPTG (Life Technologies). The eluted DNA was then re-transformed and individual clones were isolated for sequence analysis. Mutant fusion proteins with increased solubility and activity (ability to bind coactivator) should be selected for after rounds of panning and increased stringency washes. Once the sequence of the mutant Lacl-GR LBD was identified, the same mutation was also made in the pET24 expression vector (see Example 1). The expression and partial purification of the mutant Lacl-derived GST-GR LBD fusion proteins were performed in the same manner as described in Examples 3 and 4.

FIG. 1D depicts the partial purification of E. Coli expressed GR (521-777) for several mutants isolated by the Lacl Fusion system. For solubility testing, these mutants are expressed as a fusion to 6xHis-GST using the modified pET24 expression vector. Continuing with FIG. 1D, Lane 1 contains the soluble fraction of GST-GR (521-777) F602S, Lane 2: GR (521-777) wild type, Lane 3: GST-GR (521-777) A580T/F602L, Lane 4: GST-GR (521-777) A574T, Lane 5: GST-GR (521-777) Q615H, and Lane 6: GST-GR (521-777) Q615L. Molecular weight markers (kD) are shown in Lane M. TABLE 3 Statistics of Crystallographic Data and Structure GR/TIF2 with Crystals dexamethasone Space group P6₁ resolution (Å) 20.0-2.8 Unique reflections (N) 18,923 completeness (%) 99.7 I/σ (last shell) 25.6 (2.2) R_(sym) ^(a) (%) 8.5 refinement statistics R factor^(b) (%) 33.4 R free (%) 29.6 r.m.s.d. 0.015 bond lengths (Å) r.m.s.d. bond 1.795 angles(degrees) Number of H2O 53 total non-hydrogen 4444 atoms r.m.s.d is the root mean square deviation from ideal geometry. ^(a)R_(sym) = Σ|lavg − li|/Σli ^(b)R_(factor) = Σ|F_(P) − F_(Pcalc)|/ΣF_(p), where F_(p) and F_(pcalc) are observed and calculated structure factors, R_(free) is calculated from a randomly chosen 8% of reflections that never be used in refinement and R_(factor) is calculated for the remaining 92% of reflections.

REFERENCES

The references listed below as well as all references cited in the specification are incorporated herein by reference to the extent that they supplement, explain, provide a background for or teach methodology, techniques and/or compositions employed herein.

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WO 99/26966 TABLE 4 ATOMIC STRUCTURE COORDINATE DATA OBTAINED FROM X-RAY DIFFRACTION FROM THE LIGAND BINDING DOMAIN OF GRα IN COMPLEX WITH DEXAMETHASONE ATOM ATOM TYPE RESIDUE PROTEIN # # X Y OCC B 1 CB GLN 527 60.207 9.806 35.497 1.00 60.77 2 CG GLN 527 60.501 11.318 35.564 1.00 60.74 3 CD GLN 527 60.595 11.993 34.172 1.00 63.52 4 OE1 GLN 527 60.493 13.224 34.058 1.00 61.80 5 NE2 GLN 527 60.794 11.187 33.121 1.00 61.21 6 C GLN 527 62.073 8.590 36.647 1.00 62.83 7 O GLN 527 63.240 8.191 36.724 1.00 59.67 8 N GLN 527 61.009 7.618 34.618 1.00 58.91 9 CA GLN 527 61.426 8.890 35.289 1.00 62.13 10 N LEU 528 61.308 8.776 37.716 1.00 62.73 11 CA LEU 528 61.816 8.538 39.064 1.00 65.02 12 CB LEU 528 62.105 9.889 39.733 1.00 62.65 13 CG LEU 528 62.864 10.872 38.813 1.00 59.23 14 CD1 LEU 528 62.071 12.198 38.675 1.00 63.52 15 CD2 LEU 528 64.283 11.105 39.356 1.00 60.04 16 C LEU 528 60.823 7.690 39.888 1.00 59.38 17 O LEU 528 60.586 6.527 39.527 1.00 63.35 18 N THR 529 60.247 8.256 40.960 1.00 60.40 19 CA THR 529 59.282 7.539 41.835 1.00 60.79 20 CB THR 529 57.841 8.227 41.847 1.00 63.67 21 OG1 THR 529 57.918 9.561 42.382 1.00 60.60 22 CG2 THR 529 56.867 7.410 42.706 1.00 62.04 23 C THR 529 59.134 6.056 41.397 1.00 61.38 24 O THR 529 58.454 5.754 40.398 1.00 59.93 25 N PRO 530 59.743 5.117 42.163 1.00 61.16 26 CD PRO 530 60.110 5.411 43.563 1.00 60.38 27 CA PRO 530 59.753 3.660 41.928 1.00 62.39 28 CB PRO 530 60.388 3.109 43.213 1.00 58.06 29 CG PRO 530 59.914 4.071 44.249 1.00 64.31 30 C PRO 530 58.453 2.927 41.537 1.00 63.39 31 O PRO 530 57.400 3.542 41.363 1.00 59.17 32 N THR 531 58.554 1.603 41.419 1.00 62.27 33 CA THR 531 57.455 0.742 40.997 1.00 61.68 34 CB THR 531 57.989 −0.404 40.058 1.00 60.38 35 OG1 THR 531 57.209 −0.461 38.853 1.00 60.25 36 CG2 THR 531 57.937 −1.760 40.757 1.00 60.67 37 C THR 531 56.629 0.125 42.117 1.00 60.82 38 O THR 531 55.533 −0.361 41.864 1.00 62.20 39 N LEU 532 57.122 0.128 43.348 1.00 60.85 40 CA LEU 532 56.324 −0.465 44.418 1.00 60.11 41 CB LEU 532 57.183 −0.775 45.637 1.00 64.22 42 CG LEU 532 56.388 −1.514 46.704 1.00 63.74 43 CD1 LEU 532 55.677 −2.694 46.082 1.00 62.66 44 CD2 LEU 532 57.317 −1.968 47.806 1.00 63.22 45 C LEU 532 55.143 0.422 44.817 1.00 62.08 46 O LEU 532 54.047 −0.075 45.061 1.00 61.27 47 N VAL 533 55.366 1.733 44.883 1.00 59.27 48 CA VAL 533 54.297 2.677 45.222 1.00 62.90 49 CB VAL 533 54.858 4.050 45.638 1.00 64.91 50 CG1 VAL 533 55.572 4.693 44.465 1.00 60.86 51 CG2 VAL 533 53.746 4.941 46.102 1.00 61.00 52 C VAL 533 53.422 2.874 43.979 1.00 62.21 53 O VAL 533 52.281 3.321 44.065 1.00 61.72 54 N SER 534 53.981 2.553 42.817 1.00 60.92 55 CA SER 534 53.249 2.665 41.564 1.00 61.24 56 CB SER 534 54.196 2.474 40.386 1.00 61.92 57 OG SER 534 53.468 2.355 39.183 1.00 61.38 58 C SER 534 52.209 1.557 41.566 1.00 64.31 59 O SER 534 51.105 1.691 41.027 1.00 62.62 60 N LEU 535 52.581 0.452 42.193 1.00 61.91 61 CA LEU 535 51.697 −0.684 42.288 1.00 60.97 62 CB LEU 535 52.479 −1.922 42.730 1.00 66.65 63 CG LEU 535 51.949 −3.225 42.131 1.00 63.58 64 CD1 LEU 535 52.657 −3.505 40.827 1.00 62.14 65 CD2 LEU 535 52.175 −4.364 43.090 1.00 61.95 66 C LEU 535 50.588 −0.353 43.285 1.00 59.91 67 O LEU 535 49.432 −0.684 43.060 1.00 63.02 68 N LEU 536 50.933 0.315 44.381 1.00 62.58 69 CA LEU 536 49.932 0.683 45.376 1.00 59.17 70 CB LEU 536 50.583 1.413 46.541 1.00 61.74 71 CG LEU 536 51.501 0.625 47.460 1.00 58.87 72 CD1 LEU 536 51.953 1.545 48.553 1.00 59.54 73 CD2 LEU 536 50.781 −0.575 48.045 1.00 63.64 74 C LEU 536 48.821 1.569 44.812 1.00 63.31 75 O LEU 536 47.672 1.489 45.256 1.00 61.67 76 N GLU 537 49.171 2.415 43.845 1.00 59.21 77 CA GLU 537 48.231 3.343 43.213 1.00 59.76 78 CB GLU 537 48.984 4.292 42.302 1.00 59.81 79 CG GLU 537 48.816 5.744 42.625 1.00 60.10 80 CD GLU 537 48.907 6.616 41.385 1.00 64.34 81 OE1 GLU 537 47.868 6.813 40.707 1.00 57.41 82 OE2 GLU 537 50.024 7.091 41.084 1.00 62.84 83 C GLU 537 47.139 2.698 42.371 1.00 61.66 84 O GLU 537 45.973 3.101 42.433 1.00 60.28 85 N VAL 538 47.536 1.717 41.564 1.00 60.48 86 CA VAL 538 46.606 1.045 40.674 1.00 63.41 87 CB VAL 538 47.325 0.448 39.442 1.00 64.15 88 CG1 VAL 538 48.334 1.444 38.903 1.00 60.29 89 CG2 VAL 538 47.973 −0.883 39.797 1.00 63.88 90 C VAL 538 45.768 −0.046 41.311 1.00 57.99 91 O VAL 538 44.828 −0.530 40.683 1.00 58.71 92 N ILE 539 46.094 −0.454 42.535 1.00 61.14 93 CA ILE 539 45.282 −1.484 43.186 1.00 60.23 94 CB ILE 539 46.141 −2.499 44.010 1.00 65.32 95 CG2 ILE 539 47.243 −3.066 43.140 1.00 61.32 96 CG1 ILE 539 46.775 −1.833 45.228 1.00 63.80 97 CD1 ILE 539 47.356 −2.833 46.207 1.00 60.85 98 C ILE 539 44.259 −0.811 44.097 1.00 61.40 99 O ILE 539 43.321 −1.447 44.573 1.00 63.49 100 N GLU 540 44.451 0.489 44.310 1.00 61.12 101 CA GLU 540 43.584 1.307 45.153 1.00 60.76 102 CB GLU 540 44.109 2.753 45.173 1.00 58.26 103 CG GLU 540 43.466 3.684 46.191 1.00 61.15 104 CD GLU 540 43.598 3.183 47.619 1.00 61.95 105 OE1 GLU 540 44.656 2.591 47.950 1.00 59.71 106 OE2 GLU 540 42.649 3.397 48.410 1.00 62.96 107 C GLU 540 42.169 1.264 44.585 1.00 61.78 108 O GLU 540 41.928 1.709 43.459 1.00 61.36 109 N PRO 541 41.214 0.713 45.352 1.00 63.77 110 CD PRO 541 41.365 0.053 46.659 1.00 58.98 111 CA PRO 541 39.830 0.632 44.876 1.00 60.14 112 CB PRO 541 39.131 −0.149 45.988 1.00 59.62 113 CG PRO 541 39.978 0.122 47.195 1.00 60.56 114 C PRO 541 39.180 1.991 44.592 1.00 62.36 115 O PRO 541 39.455 2.982 45.283 1.00 59.45 116 N GLU 542 38.332 2.039 43.563 1.00 60.43 117 CA GLU 542 37.653 3.279 43.198 1.00 62.04 118 CB GLU 542 37.091 3.201 41.770 1.00 62.84 119 CG GLU 542 36.130 2.050 41.511 1.00 63.24 120 CD GLU 542 35.745 1.911 40.031 1.00 63.39 121 OE1 GLU 542 36.622 2.095 39.153 1.00 60.50 122 OE2 GLU 542 34.568 1.599 39.743 1.00 59.31 123 C GLU 542 36.548 3.515 44.208 1.00 63.11 124 O GLU 542 35.941 2.564 44.697 1.00 59.70 125 N VAL 543 36.304 4.783 44.528 1.00 61.53 126 CA VAL 543 35.299 5.148 45.518 1.00 63.47 127 CB VAL 543 35.334 6.661 45.801 1.00 62.60 128 CG1 VAL 543 34.467 6.984 46.987 1.00 60.93 129 CG2 VAL 543 36.762 7.103 46.064 1.00 59.59 130 C VAL 543 33.886 4.748 45.126 1.00 61.39 131 O VAL 543 33.495 4.877 43.965 1.00 60.79 132 N LEU 544 33.128 4.267 46.109 1.00 62.56 133 CA LEU 544 31.759 3.836 45.882 1.00 60.63 134 CB LEU 544 31.501 2.486 46.547 1.00 63.18 135 CG LEU 544 32.666 1.512 46.682 1.00 61.92 136 CD1 LEU 544 33.702 2.114 47.638 1.00 62.67 137 CD2 LEU 544 32.163 0.172 47.225 1.00 61.02 138 C LEU 544 30.754 4.844 46.423 1.00 58.48 139 O LEU 544 31.097 5.715 47.225 1.00 59.01 140 N TYR 545 29.508 4.698 45.974 1.00 60.35 141 CA TYR 545 28.394 5.559 46.356 1.00 58.86 142 CB TYR 545 27.616 5.977 45.105 1.00 59.62 143 CG TYR 545 28.421 6.799 44.122 1.00 60.54 144 CD1 TYR 545 29.815 6.803 44.162 1.00 59.00 145 CE1 TYR 545 30.561 7.563 43.270 1.00 61.22 146 CD2 TYR 545 27.791 7.579 43.153 1.00 63.95 147 CE2 TYR 545 28.534 8.348 42.256 1.00 59.17 148 CZ TYR 545 29.914 8.336 42.325 1.00 60.43 149 OH TYR 545 30.654 9.120 41.478 1.00 60.96 150 C TYR 545 27.501 4.743 47.269 1.00 64.48 151 O TYR 545 27.449 3.517 47.151 1.00 60.43 152 N ALA 546 26.789 5.415 48.168 1.00 62.22 153 CA ALA 546 25.918 4.720 49.112 1.00 61.72 154 CB ALA 546 25.780 5.540 50.378 1.00 60.83 155 C ALA 546 24.536 4.377 48.570 1.00 61.54 156 O ALA 546 23.886 3.461 49.065 1.00 58.65 157 N GLY 547 24.089 5.100 47.549 1.00 60.89 158 CA GLY 547 22.768 4.841 47.014 1.00 59.44 159 C GLY 547 21.765 5.212 48.088 1.00 59.45 160 O GLY 547 20.849 4.460 48.392 1.00 58.64 161 N TYR 548 21.966 6.387 48.671 1.00 59.64 162 CA TYR 548 21.119 6.921 49.733 1.00 61.47 163 CB TYR 548 21.912 7.970 50.520 1.00 64.12 164 CG TYR 548 21.244 8.421 51.783 1.00 58.90 165 CD1 TYR 548 21.049 7.534 52.833 1.00 61.61 166 CE1 TYR 548 20.414 7.927 53.992 1.00 63.67 167 CD2 TYR 548 20.785 9.726 51.926 1.00 60.05 168 CE2 TYR 548 20.144 10.129 53.084 1.00 60.57 169 CZ TYR 548 19.964 9.218 54.112 1.00 64.94 170 OH TYR 548 19.319 9.579 55.262 1.00 63.47 171 C TYR 548 19.907 7.569 49.080 1.00 63.87 172 O TYR 548 19.755 7.481 47.867 1.00 60.53 173 N ASP 549 19.043 8.207 49.871 1.00 60.86 174 CA ASP 549 17.881 8.882 49.307 1.00 62.83 175 CB ASP 549 16.590 8.410 49.958 1.00 61.82 176 CG ASP 549 15.487 8.213 48.935 1.00 59.25 177 OD1 ASP 549 14.321 7.942 49.306 1.00 61.06 178 OD2 ASP 549 15.810 8.328 47.734 1.00 61.75 179 C ASP 549 17.979 10.402 49.411 1.00 62.83 180 O ASP 549 18.158 11.075 48.400 1.00 60.57 181 N SER 550 17.875 10.954 50.617 1.00 59.81 182 CA SER 550 17.953 12.415 50.793 1.00 62.38 183 CB SER 550 19.325 12.951 50.386 1.00 56.99 184 OG SER 550 19.438 13.020 48.978 1.00 62.06 185 C SER 550 16.894 13.126 49.957 1.00 62.44 186 O SER 550 16.893 14.350 49.843 1.00 61.89 187 N SER 551 16.018 12.343 49.343 1.00 61.48 188 CA SER 551 14.924 12.875 48.557 1.00 60.05 189 CB SER 551 14.507 11.886 47.487 1.00 62.39 190 OG SER 551 13.838 10.800 48.100 1.00 61.65 191 C SER 551 13.850 12.904 49.615 1.00 60.87 192 O SER 551 12.799 13.512 49.452 1.00 59.31 193 N VAL 552 14.142 12.200 50.703 1.00 61.91 194 CA VAL 552 13.252 12.096 51.849 1.00 60.13 195 CB VAL 552 12.584 10.695 51.895 1.00 60.55 196 CG1 VAL 552 11.242 10.744 51.187 1.00 59.77 197 CG2 VAL 552 13.461 9.674 51.211 1.00 62.73 198 C VAL 552 14.035 12.388 53.141 1.00 58.44 199 O VAL 552 15.269 12.482 53.116 1.00 60.59 200 N PRO 553 13.326 12.571 54.278 1.00 59.91 201 CD PRO 553 11.861 12.614 54.440 1.00 61.19 202 CA PRO 553 13.974 12.859 55.559 1.00 59.95 203 CB PRO 553 12.865 12.572 56.556 1.00 62.02 204 CG PRO 553 11.701 13.166 55.851 1.00 62.09 205 C PRO 553 15.263 12.093 55.839 1.00 62.80 206 O PRO 553 15.525 11.035 55.259 1.00 61.14 207 N ASP 554 16.058 12.646 56.748 1.00 58.85 208 CA ASP 554 17.357 12.084 57.104 1.00 60.06 209 CB ASP 554 18.462 13.098 56.755 1.00 61.56 210 CG ASP 554 18.836 13.106 55.280 1.00 62.42 211 OD1 ASP 554 17.961 12.964 54.390 1.00 59.77 212 OD2 ASP 554 20.038 13.286 55.014 1.00 59.95 213 C ASP 554 17.535 11.703 58.575 1.00 56.92 214 O ASP 554 18.402 12.273 59.229 1.00 61.20 215 N SER 555 16.767 10.761 59.116 1.00 62.60 216 CA SER 555 16.970 10.398 60.526 1.00 63.72 217 CB SER 555 15.998 9.296 60.948 1.00 63.32 218 OG SER 555 16.267 8.089 60.255 1.00 60.75 219 C SER 555 18.404 9.905 60.749 1.00 61.32 220 O SER 555 19.093 9.556 59.794 1.00 59.49 221 N THR 556 18.855 9.877 62.002 1.00 63.20 222 CA THR 556 20.211 9.407 62.308 1.00 62.68 223 CB THR 556 20.554 9.487 63.826 1.00 62.64 224 OG1 THR 556 20.893 10.831 64.183 1.00 62.26 225 CG2 THR 556 21.739 8.582 64.158 1.00 62.40 226 C THR 556 20.387 7.955 61.902 1.00 62.17 227 O THR 556 21.196 7.633 61.030 1.00 63.77 228 N TRP 557 19.624 7.082 62.554 1.00 63.04 229 CA TRP 557 19.696 5.652 62.294 1.00 60.39 230 CB TRP 557 18.505 4.923 62.964 1.00 61.26 231 CG TRP 557 17.324 4.805 62.064 1.00 64.02 232 CD2 TRP 557 17.074 3.747 61.123 1.00 60.71 233 CE2 TRP 557 15.970 4.142 60.332 1.00 58.32 234 CE3 TRP 557 17.684 2.511 60.865 1.00 62.45 235 CD1 TRP 557 16.378 5.760 61.825 1.00 60.50 236 NE1 TRP 557 15.562 5.373 60.780 1.00 59.73 237 CZ2 TRP 557 15.464 3.341 59.296 1.00 61.79 238 CZ3 TRP 557 17.184 1.716 59.836 1.00 62.55 239 CH2 TRP 557 16.084 2.136 59.065 1.00 57.76 240 C TRP 557 19.731 5.362 60.783 1.00 61.95 241 O TRP 557 20.479 4.493 60.332 1.00 59.61 242 N ARG 558 18.946 6.099 60.001 1.00 61.85 243 CA ARG 558 18.898 5.873 58.555 1.00 64.57 244 CB ARG 558 17.744 6.651 57.926 1.00 59.03 245 CG ARG 558 17.303 6.107 56.582 1.00 62.63 246 CD ARG 558 16.012 6.780 56.133 1.00 59.07 247 NE ARG 558 16.221 7.958 55.288 1.00 61.76 248 CZ ARG 558 16.594 7.911 54.011 1.00 63.52 249 NH1 ARG 558 16.805 6.745 53.420 1.00 63.08 250 NH2 ARG 558 16.750 9.031 53.319 1.00 60.97 251 C ARG 558 20.200 6.222 57.841 1.00 64.20 252 O ARG 558 20.573 5.566 56.869 1.00 65.47 253 N ILE 559 20.877 7.266 58.307 1.00 62.87 254 CA ILE 559 22.156 7.678 57.726 1.00 59.66 255 CB ILE 559 22.639 9.040 58.329 1.00 62.98 256 CG2 ILE 559 24.101 9.278 57.993 1.00 59.64 257 CG1 ILE 559 21.794 10.196 57.791 1.00 61.72 258 CD1 ILE 559 22.091 10.556 56.351 1.00 60.58 259 C ILE 559 23.152 6.585 58.119 1.00 62.05 260 O ILE 559 23.838 5.995 57.274 1.00 61.48 261 N MET 560 23.188 6.332 59.425 1.00 60.47 262 CA MET 560 24.056 5.340 60.036 1.00 59.72 263 CB MET 560 23.799 5.286 61.554 1.00 61.50 264 CG MET 560 24.863 6.016 62.358 1.00 59.68 265 SD MET 560 24.765 5.946 64.183 1.00 62.00 266 CE MET 560 25.827 7.029 64.314 1.00 56.75 267 C MET 560 23.910 3.950 59.421 1.00 63.13 268 O MET 560 24.908 3.299 59.122 1.00 60.43 269 N THR 561 22.680 3.493 59.215 1.00 59.86 270 CA THR 561 22.487 2.183 58.619 1.00 62.03 271 CB THR 561 21.005 1.771 58.603 1.00 60.73 272 OG1 THR 561 20.483 1.777 59.938 1.00 58.44 273 CG2 THR 561 20.862 0.370 58.025 1.00 59.27 274 C THR 561 23.005 2.192 57.190 1.00 62.25 275 O THR 561 23.565 1.211 56.724 1.00 59.53 276 N THR 562 22.813 3.296 56.482 1.00 61.35 277 CA THR 562 23.305 3.365 55.112 1.00 62.18 278 CB THR 562 22.728 4.593 54.342 1.00 58.86 279 OG1 THR 562 21.338 4.375 54.051 1.00 58.36 280 CG2 THR 562 23.473 4.805 53.033 1.00 58.66 281 C THR 562 24.830 3.432 55.157 1.00 62.40 282 O THR 562 25.509 3.011 54.225 1.00 59.62 283 N LEU 563 25.374 3.949 56.252 1.00 60.06 284 CA LEU 563 26.825 4.026 56.382 1.00 61.98 285 CB LEU 563 27.230 5.045 57.451 1.00 59.10 286 CG LEU 563 27.004 6.519 57.119 1.00 62.03 287 CD1 LEU 563 27.667 7.377 58.180 1.00 59.83 288 CD2 LEU 563 27.574 6.827 55.745 1.00 63.51 289 C LEU 563 27.406 2.657 56.730 1.00 63.21 290 O LEU 563 28.592 2.410 56.529 1.00 59.14 291 N ASN 564 26.567 1.773 57.264 1.00 59.68 292 CA ASN 564 27.001 0.427 57.606 1.00 62.50 293 CB ASN 564 26.110 −0.166 58.689 1.00 61.63 294 CG ASN 564 26.456 0.349 60.058 1.00 62.37 295 OD1 ASN 564 27.625 0.513 60.381 1.00 62.36 296 ND2 ASN 564 25.447 0.590 60.881 1.00 59.03 297 C ASN 564 26.949 −0.442 56.356 1.00 61.40 298 O ASN 564 27.823 −1.266 56.121 1.00 61.63 299 N MET 565 25.923 −0.251 55.543 1.00 62.42 300 CA MET 565 25.804 −1.022 54.320 1.00 63.45 301 CB MET 565 24.483 −0.701 53.632 1.00 59.10 302 CG MET 565 23.266 −0.999 54.488 1.00 62.52 303 SD MET 565 23.154 −2.742 54.883 1.00 63.35 304 CE MET 565 22.918 −2.702 56.627 1.00 60.16 305 C MET 565 26.967 −0.669 53.410 1.00 62.27 306 O MET 565 27.475 −1.509 52.677 1.00 62.01 307 N LEU 566 27.382 0.590 53.462 1.00 62.25 308 CA LEU 566 28.495 1.064 52.656 1.00 60.20 309 CB LEU 566 28.596 2.594 52.741 1.00 59.50 310 CG LEU 566 29.801 3.267 52.076 1.00 64.18 311 CD1 LEU 566 29.685 3.195 50.565 1.00 61.46 312 CD2 LEU 566 29.869 4.700 52.516 1.00 62.10 313 C LEU 566 29.756 0.424 53.218 1.00 62.85 314 O LEU 566 30.576 −0.116 52.474 1.00 60.20 315 N GLY 567 29.886 0.477 54.542 1.00 59.45 316 CA GLY 567 31.040 −0.095 55.207 1.00 59.94 317 C GLY 567 31.316 −1.516 54.768 1.00 60.71 318 O GLY 567 32.461 −1.890 54.520 1.00 59.79 319 N GLY 568 30.261 −2.310 54.667 1.00 61.99 320 CA GLY 568 30.417 −3.687 54.254 1.00 59.73 321 C GLY 568 31.050 −3.836 52.888 1.00 60.65 322 O GLY 568 32.008 −4.590 52.724 1.00 63.15 323 N ARG 569 30.529 −3.112 51.907 1.00 58.99 324 CA ARG 569 31.049 −3.208 50.557 1.00 60.81 325 CB ARG 569 30.109 −2.483 49.600 1.00 60.57 326 CG ARG 569 28.696 −3.029 49.701 1.00 61.60 327 CD ARG 569 27.806 −2.602 48.556 1.00 64.73 328 NE ARG 569 27.561 −1.168 48.564 1.00 61.17 329 CZ ARG 569 27.939 −0.352 47.590 1.00 60.00 330 NH1 ARG 569 28.577 −0.841 46.532 1.00 60.46 331 NH2 ARG 569 27.681 0.946 47.680 1.00 63.69 332 C ARG 569 32.462 −2.676 50.447 1.00 61.15 333 O ARG 569 33.249 −3.137 49.620 1.00 60.59 334 N GLN 570 32.788 −1.713 51.295 1.00 60.73 335 CA GLN 570 34.123 −1.132 51.300 1.00 62.31 336 CB GLN 570 34.143 0.150 52.120 1.00 59.04 337 CG GLN 570 33.608 1.361 51.417 1.00 62.03 338 CD GLN 570 33.782 2.606 52.247 1.00 56.35 339 OE1 GLN 570 33.460 3.698 51.801 1.00 62.86 340 NE2 GLN 570 34.295 2.449 53.467 1.00 63.17 341 C GLN 570 35.144 −2.093 51.882 1.00 61.15 342 O GLN 570 36.293 −2.134 51.441 1.00 60.50 343 N VAL 571 34.732 −2.837 52.903 1.00 60.99 344 CA VAL 571 35.615 −3.792 53.554 1.00 61.91 345 CB VAL 571 35.054 −4.200 54.930 1.00 58.42 346 CG1 VAL 571 35.822 −5.393 55.485 1.00 61.27 347 CG2 VAL 571 35.160 −3.007 55.891 1.00 60.58 348 C VAL 571 35.805 −5.007 52.665 1.00 62.66 349 O VAL 571 36.698 −5.820 52.885 1.00 58.99 350 N ILE 572 34.958 −5.116 51.652 1.00 63.61 351 CA ILE 572 35.042 −6.206 50.695 1.00 63.76 352 CB ILE 572 33.649 −6.539 50.103 1.00 60.98 353 CG2 ILE 572 33.794 −7.443 48.883 1.00 63.63 354 CG1 ILE 572 32.782 −7.192 51.183 1.00 61.03 355 CD1 ILE 572 31.346 −7.366 50.801 1.00 62.17 356 C ILE 572 35.999 −5.772 49.589 1.00 60.35 357 O ILE 572 36.733 −6.587 49.042 1.00 62.13 358 N ALA 573 35.984 −4.481 49.265 1.00 62.76 359 CA ALA 573 36.879 −3.936 48.251 1.00 58.47 360 CB ALA 573 36.502 −2.496 47.940 1.00 61.48 361 C ALA 573 38.271 −3.997 48.872 1.00 61.14 362 O ALA 573 39.294 −4.088 48.180 1.00 60.46 363 N ALA 574 38.273 −3.964 50.200 1.00 60.84 364 CA ALA 574 39.477 −4.008 51.003 1.00 61.42 365 CB ALA 574 39.098 −3.888 52.465 1.00 60.18 366 C ALA 574 40.294 −5.282 50.771 1.00 58.96 367 O ALA 574 41.506 −5.217 50.518 1.00 61.38 368 N VAL 575 39.631 −6.435 50.861 1.00 59.99 369 CA VAL 575 40.296 −7.720 50.664 1.00 59.60 370 CB VAL 575 39.309 −8.898 50.732 1.00 56.06 371 CG1 VAL 575 40.070 −10.197 50.570 1.00 62.55 372 CG2 VAL 575 38.547 −8.880 52.057 1.00 63.34 373 C VAL 575 41.009 −7.779 49.318 1.00 60.96 374 O VAL 575 42.222 −7.981 49.264 1.00 62.47 375 N LYS 576 40.265 −7.584 48.236 1.00 59.97 376 CA LYS 576 40.851 −7.628 46.901 1.00 62.25 377 CB LYS 576 39.770 −7.391 45.860 1.00 60.99 378 CG LYS 576 40.115 −7.866 44.462 1.00 61.35 379 CD LYS 576 38.905 −7.708 43.568 1.00 63.13 380 CE LYS 576 37.667 −8.234 44.276 1.00 62.07 381 NZ LYS 576 36.420 −7.912 43.531 1.00 59.76 382 C LYS 576 41.957 −6.593 46.742 1.00 63.69 383 O LYS 576 42.673 −6.573 45.742 1.00 59.32 384 N TRP 577 42.074 −5.723 47.734 1.00 62.59 385 CA TRP 577 43.091 −4.694 47.734 1.00 62.15 386 CB TRP 577 42.556 −3.432 48.424 1.00 60.50 387 CG TRP 577 43.620 −2.458 48.780 1.00 63.03 388 CD2 TRP 577 44.140 −2.200 50.090 1.00 58.79 389 CE2 TRP 577 45.189 −1.272 49.945 1.00 64.04 390 CE3 TRP 577 43.824 −2.668 51.372 1.00 60.56 391 CD1 TRP 577 44.346 −1.698 47.924 1.00 62.09 392 NE1 TRP 577 45.293 −0.983 48.611 1.00 61.93 393 CZ2 TRP 577 45.930 −0.798 51.032 1.00 61.40 394 CZ3 TRP 577 44.566 −2.197 52.458 1.00 59.59 395 CH2 TRP 577 45.607 −1.271 52.277 1.00 61.92 396 C TRP 577 44.263 −5.272 48.509 1.00 64.09 397 O TRP 577 45.403 −5.238 48.055 1.00 61.89 398 N ALA 578 43.958 −5.824 49.678 1.00 60.10 399 CA ALA 578 44.974 −6.411 50.541 1.00 61.99 400 CB ALA 578 44.342 −6.937 51.828 1.00 57.97 401 C ALA 578 45.704 −7.526 49.828 1.00 61.84 402 O ALA 578 46.890 −7.718 50.034 1.00 60.47 403 N LYS 579 44.988 −8.251 48.979 1.00 61.79 404 CA LYS 579 45.573 −9.354 48.233 1.00 60.65 405 CB LYS 579 44.472 −10.320 47.784 1.00 62.20 406 CG LYS 579 43.479 −10.656 48.893 1.00 63.14 407 CD LYS 579 42.688 −11.944 48.636 1.00 58.27 408 CE LYS 579 41.775 −11.862 47.419 1.00 58.47 409 NZ LYS 579 41.093 −13.167 47.129 1.00 62.99 410 C LYS 579 46.389 −8.895 47.024 1.00 61.02 411 O LYS 579 47.014 −9.713 46.356 1.00 63.16 412 N ALA 580 46.383 −7.596 46.738 1.00 61.84 413 CA ALA 580 47.153 −7.079 45.610 1.00 58.94 414 CB ALA 580 46.339 −6.062 44.817 1.00 61.14 415 C ALA 580 48.439 −6.446 46.137 1.00 60.40 416 O ALA 580 49.378 −6.190 45.374 1.00 60.45 417 N ILE 581 48.465 −6.197 47.445 1.00 60.82 418 CA ILE 581 49.631 −5.631 48.111 1.00 60.29 419 CB ILE 581 49.375 −5.412 49.630 1.00 58.24 420 CG2 ILE 581 50.654 −4.997 50.324 1.00 63.40 421 CG1 ILE 581 48.295 −4.353 49.847 1.00 62.12 422 CD1 ILE 581 47.769 −4.324 51.257 1.00 62.13 423 C ILE 581 50.690 −6.706 47.965 1.00 62.02 424 O ILE 581 50.541 −7.805 48.500 1.00 61.29 425 N PRO 582 51.773 −6.412 47.233 1.00 62.24 426 CD PRO 582 52.137 −5.123 46.623 1.00 61.16 427 CA PRO 582 52.837 −7.397 47.041 1.00 64.30 428 CB PRO 582 53.983 −6.563 46.486 1.00 61.32 429 CG PRO 582 53.294 −5.515 45.720 1.00 57.84 430 C PRO 582 53.208 −8.082 48.341 1.00 62.26 431 O PRO 582 53.291 −7.451 49.390 1.00 61.55 432 N GLY 583 53.413 −9.386 48.268 1.00 60.04 433 CA GLY 583 53.788 −10.138 49.447 1.00 63.24 434 C GLY 583 52.721 −10.313 50.509 1.00 58.28 435 O GLY 583 52.976 −10.962 51.519 1.00 61.03 436 N PHE 584 51.527 −9.758 50.320 1.00 59.53 437 CA PHE 584 50.517 −9.932 51.354 1.00 60.33 438 CB PHE 584 49.356 −8.960 51.200 1.00 59.83 439 CG PHE 584 48.314 −9.107 52.276 1.00 62.69 440 CD1 PHE 584 48.583 −8.699 53.576 1.00 65.80 441 CD2 PHE 584 47.075 −9.677 52.000 1.00 59.15 442 CE1 PHE 584 47.636 −8.854 54.586 1.00 63.90 443 CE2 PHE 584 46.123 −9.837 53.000 1.00 62.77 444 CZ PHE 584 46.405 −9.423 54.296 1.00 62.23 445 C PHE 584 49.960 −11.336 51.359 1.00 59.87 446 O PHE 584 49.874 −11.967 52.415 1.00 60.23 447 N ARG 585 49.584 −11.848 50.193 1.00 61.22 448 CA ARG 585 49.021 −13.183 50.207 1.00 62.87 449 CB ARG 585 48.025 −13.405 49.042 1.00 61.05 450 CG ARG 585 48.486 −13.212 47.602 1.00 62.14 451 CD ARG 585 47.253 −13.326 46.690 1.00 59.51 452 NE ARG 585 46.321 −14.325 47.226 1.00 57.83 453 CZ ARG 585 45.253 −14.826 46.592 1.00 62.40 454 NH1 ARG 585 44.934 −14.430 45.360 1.00 64.51 455 NH2 ARG 585 44.509 −15.752 47.194 1.00 62.15 456 C ARG 585 50.053 −14.290 50.303 1.00 61.04 457 O ARG 585 49.781 −15.436 49.962 1.00 59.18 458 N ASN 586 51.232 −13.935 50.811 1.00 59.32 459 CA ASN 586 52.319 −14.893 51.021 1.00 62.11 460 CB ASN 586 53.659 −14.329 50.545 1.00 57.88 461 CG ASN 586 53.910 −14.596 49.071 1.00 62.73 462 OD1 ASN 586 54.772 −13.964 48.450 1.00 64.87 463 ND2 ASN 586 53.164 −15.551 48.504 1.00 63.32 464 C ASN 586 52.396 −15.218 52.503 1.00 61.24 465 O ASN 586 53.093 −16.138 52.916 1.00 62.45 466 N LEU 587 51.692 −14.446 53.314 1.00 62.98 467 CA LEU 587 51.677 −14.732 54.735 1.00 63.89 468 CB LEU 587 51.210 −13.502 55.522 1.00 63.58 469 CG LEU 587 52.163 −12.299 55.501 1.00 63.59 470 CD1 LEU 587 51.405 −11.009 55.348 1.00 58.78 471 CD2 LEU 587 52.967 −12.280 56.773 1.00 60.86 472 C LEU 587 50.679 −15.879 54.848 1.00 61.92 473 O LEU 587 50.000 −16.209 53.865 1.00 61.57 474 N HIS 588 50.598 −16.497 56.024 1.00 57.84 475 CA HIS 588 49.676 −17.609 56.235 1.00 62.30 476 CB HIS 588 49.674 −18.016 57.710 1.00 63.47 477 CG HIS 588 49.180 −19.411 57.962 1.00 62.99 478 CD2 HIS 588 49.817 −20.502 58.447 1.00 58.47 479 ND1 HIS 588 47.886 −19.808 57.705 1.00 57.63 480 CE1 HIS 588 47.748 −21.083 58.021 1.00 60.07 481 NE2 HIS 588 48.905 −21.527 58.474 1.00 61.65 482 C HIS 588 48.304 −17.100 55.839 1.00 61.24 483 O HIS 588 48.137 −15.900 55.641 1.00 58.81 484 N LEU 589 47.325 −17.990 55.714 1.00 60.37 485 CA LEU 589 45.990 −17.542 55.346 1.00 63.23 486 CB LEU 589 45.219 −18.626 54.588 1.00 60.24 487 CG LEU 589 44.233 −18.127 53.516 1.00 59.80 488 CD1 LEU 589 43.798 −19.286 52.630 1.00 65.35 489 CD2 LEU 589 43.025 −17.486 54.148 1.00 61.31 490 C LEU 589 45.249 −17.184 56.616 1.00 59.85 491 O LEU 589 44.150 −16.645 56.563 1.00 59.20 492 N ASP 590 45.852 −17.469 57.763 1.00 60.93 493 CA ASP 590 45.200 −17.158 59.027 1.00 61.82 494 CB ASP 590 45.551 −18.204 60.097 1.00 62.69 495 CG ASP 590 44.823 −19.529 59.898 1.00 58.29 496 OD1 ASP 590 44.642 −19.955 58.738 1.00 59.06 497 OD2 ASP 590 44.447 −20.159 60.910 1.00 64.34 498 C ASP 590 45.608 −15.771 59.504 1.00 59.77 499 O ASP 590 44.915 −15.153 60.314 1.00 60.73 500 N ASP 591 46.734 −15.278 59.001 1.00 59.62 501 CA ASP 591 47.211 −13.960 59.401 1.00 61.48 502 CB ASP 591 48.733 −13.861 59.240 1.00 60.79 503 CG ASP 591 49.479 −14.900 60.065 1.00 57.79 504 OD1 ASP 591 49.012 −15.239 61.176 1.00 66.77 505 OD2 ASP 591 50.543 −15.366 59.606 1.00 65.51 506 C ASP 591 46.531 −12.927 58.529 1.00 62.56 507 O ASP 591 46.255 −11.812 58.967 1.00 59.26 508 N GLN 592 46.278 −13.323 57.285 1.00 62.10 509 CA GLN 592 45.613 −12.473 56.316 1.00 61.30 510 CB GLN 592 45.432 −13.227 54.998 1.00 62.26 511 CG GLN 592 46.751 −13.456 54.277 1.00 60.59 512 CD GLN 592 46.595 −14.100 52.909 1.00 59.32 513 OE1 GLN 592 45.597 −13.887 52.213 1.00 62.27 514 NE2 GLN 592 47.600 −14.875 52.505 1.00 62.12 515 C GLN 592 44.269 −12.097 56.906 1.00 64.75 516 O GLN 592 43.768 −10.993 56.706 1.00 62.08 517 N MET 593 43.701 −13.028 57.660 1.00 59.14 518 CA MET 593 42.413 −12.815 58.302 1.00 61.78 519 CB MET 593 41.740 −14.162 58.597 1.00 58.91 520 CG MET 593 41.290 −14.935 57.357 1.00 64.30 521 SD MET 593 40.510 −16.524 57.776 1.00 58.06 522 CE MET 593 39.514 −16.029 59.273 1.00 61.88 523 C MET 593 42.571 −12.014 59.594 1.00 61.38 524 O MET 593 41.802 −11.089 59.837 1.00 60.42 525 N THR 594 43.565 −12.361 60.415 1.00 61.83 526 CA THR 594 43.781 −11.648 61.674 1.00 61.88 527 CB THR 594 44.924 −12.267 62.518 1.00 57.74 528 OG1 THR 594 45.252 −13.571 62.023 1.00 65.18 529 CG2 THR 594 44.489 −12.393 63.977 1.00 62.23 530 C THR 594 44.127 −10.194 61.378 1.00 62.61 531 O THR 594 43.673 −9.279 62.071 1.00 60.17 532 N LEU 595 44.927 −9.987 60.337 1.00 60.31 533 CA LEU 595 45.325 −8.647 59.938 1.00 61.48 534 CB LEU 595 46.372 −8.712 58.826 1.00 62.70 535 CG LEU 595 47.788 −9.074 59.266 1.00 60.61 536 CD1 LEU 595 48.711 −9.054 58.067 1.00 63.20 537 CD2 LEU 595 48.268 −8.083 60.316 1.00 62.58 538 C LEU 595 44.128 −7.823 59.475 1.00 63.38 539 O LEU 595 43.835 −6.779 60.051 1.00 60.70 540 N LEU 596 43.439 −8.290 58.436 1.00 60.66 541 CA LEU 596 42.282 −7.571 57.924 1.00 60.47 542 CB LEU 596 41.703 −8.278 56.699 1.00 60.10 543 CG LEU 596 42.351 −7.811 55.392 1.00 60.73 544 CD1 LEU 596 42.036 −8.767 54.254 1.00 59.40 545 CD2 LEU 596 41.859 −6.407 55.073 1.00 62.48 546 C LEU 596 41.223 −7.424 58.989 1.00 58.32 547 O LEU 596 40.451 −6.480 58.965 1.00 61.48 548 N GLN 597 41.201 −8.354 59.935 1.00 62.48 549 CA GLN 597 40.230 −8.327 61.031 1.00 64.28 550 CB GLN 597 40.128 −9.712 61.685 1.00 59.49 551 CG GLN 597 38.936 −10.561 61.279 1.00 64.66 552 CD GLN 597 38.972 −11.940 61.920 1.00 60.50 553 OE1 GLN 597 39.080 −12.078 63.149 1.00 60.07 554 NE2 GLN 597 38.881 −12.975 61.087 1.00 65.01 555 C GLN 597 40.612 −7.314 62.110 1.00 61.61 556 O GLN 597 39.780 −6.933 62.932 1.00 61.06 557 N TYR 598 41.875 −6.896 62.097 1.00 64.61 558 CA TYR 598 42.418 −5.958 63.075 1.00 60.76 559 CB TYR 598 43.761 −6.468 63.588 1.00 59.35 560 CG TYR 598 43.692 −7.564 64.613 1.00 63.67 561 CD1 TYR 598 42.509 −8.257 64.850 1.00 61.84 562 CE1 TYR 598 42.451 −9.262 65.812 1.00 61.13 563 CD2 TYR 598 44.820 −7.906 65.358 1.00 61.13 564 CE2 TYR 598 44.774 −8.915 66.322 1.00 62.04 565 CZ TYR 598 43.588 −9.583 66.544 1.00 60.04 566 OH TYR 598 43.536 −10.549 67.519 1.00 62.57 567 C TYR 598 42.639 −4.553 62.549 1.00 62.24 568 O TYR 598 43.158 −3.690 63.256 1.00 61.45 569 N SER 599 42.278 −4.312 61.305 1.00 58.28 570 CA SER 599 42.491 −2.988 60.774 1.00 62.69 571 CB SER 599 43.837 −2.949 60.046 1.00 62.55 572 OG SER 599 44.008 −4.083 59.216 1.00 62.72 573 C SER 599 41.365 −2.525 59.867 1.00 64.40 574 O SER 599 41.398 −1.405 59.367 1.00 62.40 575 N TRP 600 40.358 −3.375 59.677 1.00 59.48 576 CA TRP 600 39.245 −3.026 58.807 1.00 62.88 577 CB TRP 600 38.073 −4.031 58.932 1.00 64.17 578 CG TRP 600 37.282 −3.951 60.198 1.00 62.02 579 CD2 TRP 600 36.105 −3.166 60.420 1.00 58.67 580 CE2 TRP 600 35.754 −3.311 61.781 1.00 61.68 581 CE3 TRP 600 35.314 −2.350 59.603 1.00 62.68 582 CD1 TRP 600 37.583 −4.533 61.395 1.00 58.92 583 NE1 TRP 600 36.672 −4.151 62.355 1.00 64.28 584 CZ2 TRP 600 34.648 −2.666 62.342 1.00 61.17 585 CZ3 TRP 600 34.217 −1.711 60.159 1.00 58.94 586 CH2 TRP 600 33.894 −1.871 61.516 1.00 61.08 587 C TRP 600 38.789 −1.630 59.169 1.00 62.61 588 O TRP 600 38.533 −0.805 58.308 1.00 62.45 589 N MET 601 38.744 −1.344 60.458 1.00 63.90 590 CA MET 601 38.298 −0.049 60.884 1.00 60.96 591 CB MET 601 37.968 −0.064 62.351 1.00 60.46 592 CG MET 601 37.139 1.112 62.702 1.00 61.28 593 SD MET 601 35.774 1.420 61.631 1.00 59.33 594 CE MET 601 34.684 1.638 62.889 1.00 64.63 595 C MET 601 39.225 1.129 60.577 1.00 61.08 596 O MET 601 38.758 2.167 60.114 1.00 60.27 597 N SER 602 40.521 0.979 60.854 1.00 61.23 598 CA SER 602 41.488 2.035 60.581 1.00 59.98 599 CB SER 602 42.872 1.647 61.083 1.00 60.99 600 OG SER 602 42.783 1.022 62.350 1.00 66.17 601 C SER 602 41.536 2.214 59.079 1.00 60.99 602 O SER 602 41.609 3.327 58.581 1.00 64.11 603 N LEU 603 41.494 1.108 58.351 1.00 59.44 604 CA LEU 603 41.522 1.185 56.901 1.00 61.46 605 CB LEU 603 41.402 −0.212 56.280 1.00 59.31 606 CG LEU 603 42.646 −1.097 56.346 1.00 61.54 607 CD1 LEU 603 42.415 −2.362 55.549 1.00 63.99 608 CD2 LEU 603 43.828 −0.346 55.787 1.00 63.36 609 C LEU 603 40.386 2.061 56.408 1.00 60.47 610 O LEU 603 40.599 3.062 55.731 1.00 63.39 611 N MET 604 39.173 1.688 56.784 1.00 63.54 612 CA MET 604 38.000 2.417 56.365 1.00 62.81 613 CB MET 604 36.770 1.623 56.723 1.00 58.90 614 CG MET 604 36.632 0.429 55.842 1.00 59.86 615 SD MET 604 37.633 0.438 54.374 1.00 62.53 616 CE MET 604 36.663 −0.510 53.559 1.00 60.72 617 C MET 604 37.898 3.832 56.856 1.00 60.43 618 O MET 604 37.397 4.695 56.132 1.00 62.37 619 N ALA 605 38.375 4.076 58.072 1.00 59.95 620 CA ALA 605 38.357 5.409 58.664 1.00 60.49 621 CB ALA 605 38.667 5.317 60.132 1.00 59.15 622 C ALA 605 39.381 6.309 57.985 1.00 61.50 623 O ALA 605 39.071 7.427 57.583 1.00 59.82 624 N PHE 606 40.608 5.810 57.870 1.00 63.59 625 CA PHE 606 41.700 6.554 57.258 1.00 60.15 626 CB PHE 606 42.981 5.713 57.285 1.00 63.75 627 CG PHE 606 44.237 6.490 56.999 1.00 64.30 628 CD1 PHE 606 44.723 7.424 57.913 1.00 61.77 629 CD2 PHE 606 44.957 6.265 55.829 1.00 60.74 630 CE1 PHE 606 45.910 8.118 57.665 1.00 64.00 631 CE2 PHE 606 46.145 6.955 55.575 1.00 62.47 632 CZ PHE 606 46.620 7.879 56.496 1.00 63.95 633 C PHE 606 41.362 6.933 55.825 1.00 61.96 634 O PHE 606 41.751 7.991 55.356 1.00 60.07 635 N ALA 607 40.644 6.063 55.126 1.00 62.00 636 CA ALA 607 40.264 6.338 53.745 1.00 57.50 637 CB ALA 607 39.888 5.051 53.039 1.00 59.69 638 C ALA 607 39.105 7.324 53.684 1.00 64.88 639 O ALA 607 38.931 8.030 52.703 1.00 59.60 640 N LEU 608 38.292 7.361 54.723 1.00 59.93 641 CA LEU 608 37.196 8.307 54.725 1.00 61.70 642 CB LEU 608 36.222 7.972 55.883 1.00 59.57 643 CG LEU 608 35.125 8.918 56.402 1.00 62.57 644 CD1 LEU 608 34.229 9.360 55.287 1.00 63.51 645 CD2 LEU 608 34.298 8.246 57.488 1.00 59.98 646 C LEU 608 37.862 9.662 54.935 1.00 61.71 647 O LEU 608 37.500 10.645 54.294 1.00 57.56 648 N GLY 609 38.869 9.692 55.806 1.00 59.60 649 CA GLY 609 39.583 10.920 56.086 1.00 60.49 650 C GLY 609 40.232 11.505 54.850 1.00 59.17 651 O GLY 609 40.189 12.710 54.625 1.00 61.65 652 N TRP 610 40.835 10.650 54.039 1.00 62.47 653 CA TRP 610 41.488 11.102 52.823 1.00 61.40 654 CB TRP 610 42.141 9.917 52.123 1.00 62.68 655 CG TRP 610 42.744 10.264 50.817 1.00 62.61 656 CD2 TRP 610 43.955 10.991 50.604 1.00 61.10 657 CE2 TRP 610 44.139 11.095 49.209 1.00 62.45 658 CE3 TRP 610 44.906 11.565 51.457 1.00 63.78 659 CD1 TRP 610 42.254 9.965 49.582 1.00 58.08 660 NE1 TRP 610 43.086 10.459 48.608 1.00 62.17 661 CZ2 TRP 610 45.238 11.751 48.646 1.00 60.53 662 CZ3 TRP 610 46.001 12.219 50.896 1.00 62.27 663 CH2 TRP 610 46.156 12.305 49.505 1.00 60.31 664 C TRP 610 40.517 11.797 51.874 1.00 60.80 665 O TRP 610 40.797 12.866 51.358 1.00 60.72 666 N ARG 611 39.368 11.191 51.639 1.00 61.36 667 CA ARG 611 38.412 11.790 50.738 1.00 58.33 668 CB ARG 611 37.254 10.817 50.486 1.00 62.33 669 CG ARG 611 37.684 9.490 49.873 1.00 60.18 670 CD ARG 611 36.476 8.686 49.426 1.00 59.83 671 NE ARG 611 35.604 8.333 50.544 1.00 61.17 672 CZ ARG 611 35.817 7.308 51.366 1.00 59.54 673 NH1 ARG 611 36.875 6.528 51.187 1.00 61.47 674 NH2 ARG 611 34.988 7.072 52.376 1.00 62.25 675 C ARG 611 37.898 13.128 51.277 1.00 62.93 676 O ARG 611 37.610 14.051 50.502 1.00 61.13 677 N SER 612 37.806 13.234 52.603 1.00 60.26 678 CA SER 612 37.321 14.450 53.263 1.00 63.90 679 CB SER 612 37.057 14.172 54.736 1.00 62.00 680 OG SER 612 36.011 13.234 54.875 1.00 59.62 681 C SER 612 38.263 15.637 53.137 1.00 61.68 682 O SER 612 37.831 16.776 52.975 1.00 59.32 683 N TYR 613 39.552 15.352 53.226 1.00 64.48 684 CA TYR 613 40.600 16.351 53.111 1.00 60.97 685 CB TYR 613 41.920 15.725 53.587 1.00 56.65 686 CG TYR 613 43.169 16.122 52.830 1.00 60.73 687 CD1 TYR 613 43.569 17.456 52.746 1.00 64.60 688 CE1 TYR 613 44.737 17.812 52.086 1.00 60.79 689 CD2 TYR 613 43.971 15.153 52.229 1.00 61.29 690 CE2 TYR 613 45.142 15.500 51.564 1.00 63.40 691 CZ TYR 613 45.522 16.830 51.497 1.00 61.75 692 OH TYR 613 46.690 17.173 50.854 1.00 62.46 693 C TYR 613 40.712 16.822 51.667 1.00 62.41 694 O TYR 613 40.954 17.996 51.395 1.00 61.34 695 N ARG 614 40.511 15.896 50.745 1.00 61.73 696 CA ARG 614 40.623 16.190 49.328 1.00 61.64 697 CB ARG 614 40.835 14.880 48.545 1.00 62.80 698 CG ARG 614 42.274 14.328 48.621 1.00 58.30 699 CD ARG 614 42.908 14.348 47.242 1.00 60.57 700 NE ARG 614 44.369 14.448 47.262 1.00 61.63 701 CZ ARG 614 45.056 15.421 47.868 1.00 63.66 702 NH1 ARG 614 44.414 16.386 48.521 1.00 61.59 703 NH2 ARG 614 46.389 15.451 47.797 1.00 64.70 704 C ARG 614 39.440 16.960 48.776 1.00 58.09 705 O ARG 614 39.613 17.922 48.041 1.00 63.07 706 N GLN 615 38.239 16.538 49.137 1.00 64.09 707 CA GLN 615 37.033 17.192 48.660 1.00 61.67 708 CB GLN 615 35.840 16.259 48.801 1.00 62.84 709 CG GLN 615 35.738 15.162 47.795 1.00 62.14 710 CD GLN 615 34.290 14.775 47.573 1.00 58.76 711 OE1 GLN 615 33.532 14.598 48.525 1.00 62.70 712 NE2 GLN 615 33.897 14.651 46.314 1.00 61.03 713 C GLN 615 36.677 18.478 49.396 1.00 59.82 714 O GLN 615 36.200 19.441 48.784 1.00 60.64 715 N SER 616 36.901 18.480 50.709 1.00 62.12 716 CA SER 616 36.522 19.615 51.545 1.00 62.52 717 CB SER 616 35.199 19.297 52.239 1.00 61.86 718 OG SER 616 35.408 18.310 53.240 1.00 59.96 719 C SER 616 37.514 20.090 52.612 1.00 61.77 720 O SER 616 37.110 20.501 53.703 1.00 63.13 721 N SER 617 38.804 20.026 52.321 1.00 59.65 722 CA SER 617 39.796 20.502 53.279 1.00 60.19 723 CB SER 617 39.818 22.033 53.253 1.00 60.71 724 OG SER 617 39.578 22.511 51.942 1.00 63.01 725 C SER 617 39.569 20.029 54.724 1.00 59.81 726 O SER 617 40.164 20.577 55.654 1.00 63.66 727 N ALA 618 38.700 19.036 54.903 1.00 64.87 728 CA ALA 618 38.393 18.444 56.210 1.00 62.57 729 CB ALA 618 39.673 18.327 57.064 1.00 60.83 730 C ALA 618 37.277 19.059 57.053 1.00 59.66 731 O ALA 618 37.238 18.817 58.260 1.00 60.80 732 N ASN 619 36.375 19.839 56.451 1.00 63.98 733 CA ASN 619 35.262 20.411 57.227 1.00 61.08 734 CB ASN 619 35.129 21.934 57.042 1.00 61.69 735 CG ASN 619 35.946 22.453 55.912 1.00 62.23 736 OD1 ASN 619 35.664 22.172 54.751 1.00 61.72 737 ND2 ASN 619 36.980 23.217 56.239 1.00 61.09 738 C ASN 619 33.907 19.755 56.958 1.00 60.70 739 O ASN 619 32.856 20.374 57.157 1.00 60.32 740 N LEU 620 33.951 18.505 56.500 1.00 59.87 741 CA LEU 620 32.767 17.686 56.237 1.00 59.97 742 CB LEU 620 31.777 18.358 55.270 1.00 59.52 743 CG LEU 620 32.162 19.088 53.990 1.00 61.28 744 CD1 LEU 620 31.041 18.989 52.971 1.00 64.28 745 CD2 LEU 620 32.459 20.539 54.330 1.00 65.45 746 C LEU 620 33.147 16.307 55.712 1.00 61.40 747 O LEU 620 33.869 16.178 54.720 1.00 61.10 748 N LEU 621 32.660 15.280 56.407 1.00 58.95 749 CA LEU 621 32.926 13.891 56.050 1.00 61.88 750 CB LEU 621 32.394 12.947 57.123 1.00 63.38 751 CG LEU 621 33.031 13.049 58.503 1.00 60.66 752 CD1 LEU 621 32.383 12.036 59.434 1.00 59.80 753 CD2 LEU 621 34.524 12.808 58.390 1.00 62.77 754 C LEU 621 32.283 13.540 54.728 1.00 62.48 755 O LEU 621 31.092 13.751 54.531 1.00 61.33 756 N CYS 622 33.077 12.972 53.833 1.00 59.02 757 CA CYS 622 32.585 12.609 52.523 1.00 62.42 758 CB CYS 622 33.453 13.304 51.479 1.00 59.42 759 SG CYS 622 33.715 15.064 51.889 1.00 59.94 760 C CYS 622 32.566 11.094 52.329 1.00 59.63 761 O CYS 622 33.248 10.552 51.451 1.00 58.28 762 N PHE 623 31.766 10.421 53.156 1.00 62.39 763 CA PHE 623 31.645 8.972 53.088 1.00 60.88 764 CB PHE 623 30.387 8.490 53.841 1.00 59.68 765 CG PHE 623 30.461 8.686 55.344 1.00 58.52 766 CD1 PHE 623 30.338 9.948 55.906 1.00 66.23 767 CD2 PHE 623 30.688 7.612 56.191 1.00 63.42 768 CE1 PHE 623 30.443 10.139 57.292 1.00 60.25 769 CE2 PHE 623 30.795 7.796 57.576 1.00 58.96 770 CZ PHE 623 30.673 9.059 58.124 1.00 57.60 771 C PHE 623 31.618 8.532 51.630 1.00 61.75 772 O PHE 623 32.502 7.802 51.179 1.00 60.41 773 N ALA 624 30.624 8.995 50.888 1.00 64.49 774 CA ALA 624 30.517 8.644 49.476 1.00 61.68 775 CB ALA 624 29.429 7.592 49.276 1.00 60.07 776 C ALA 624 30.179 9.912 48.700 1.00 60.93 777 O ALA 624 30.002 10.981 49.297 1.00 60.98 778 N PRO 625 30.130 9.828 47.355 1.00 62.43 779 CD PRO 625 30.706 8.811 46.459 1.00 62.52 780 CA PRO 625 29.795 11.035 46.593 1.00 59.45 781 CB PRO 625 29.949 10.582 45.146 1.00 62.18 782 CG PRO 625 31.089 9.653 45.245 1.00 59.91 783 C PRO 625 28.366 11.397 46.928 1.00 62.94 784 O PRO 625 28.111 12.382 47.622 1.00 59.36 785 N ASP 626 27.433 10.572 46.468 1.00 58.86 786 CA ASP 626 26.036 10.848 46.741 1.00 60.61 787 CB ASP 626 25.126 9.882 45.939 1.00 65.12 788 CG ASP 626 25.227 8.421 46.393 1.00 60.28 789 OD1 ASP 626 25.311 8.160 47.612 1.00 60.31 790 OD2 ASP 626 25.189 7.526 45.518 1.00 59.51 791 C ASP 626 25.680 10.825 48.248 1.00 58.60 792 O ASP 626 24.510 10.636 48.616 1.00 62.03 793 N LEU 627 26.668 11.051 49.119 1.00 63.43 794 CA LEU 627 26.392 11.020 50.552 1.00 61.63 795 CB LEU 627 26.175 9.573 51.007 1.00 58.45 796 CG LEU 627 25.874 9.407 52.496 1.00 63.46 797 CD1 LEU 627 24.401 9.669 52.770 1.00 60.41 798 CD2 LEU 627 26.241 8.013 52.919 1.00 65.05 799 C LEU 627 27.435 11.665 51.459 1.00 61.00 800 O LEU 627 28.320 10.988 51.985 1.00 62.27 801 N ILE 628 27.301 12.965 51.682 1.00 59.87 802 CA ILE 628 28.230 13.686 52.537 1.00 61.72 803 CB ILE 628 28.796 14.887 51.787 1.00 61.79 804 CG2 ILE 628 29.848 15.575 52.618 1.00 61.82 805 CG1 ILE 628 29.391 14.418 50.461 1.00 58.81 806 CD1 ILE 628 29.806 15.542 49.554 1.00 61.23 807 C ILE 628 27.541 14.162 53.815 1.00 59.57 808 O ILE 628 26.396 14.611 53.779 1.00 61.09 809 N ILE 629 28.221 14.044 54.951 1.00 60.22 810 CA ILE 629 27.638 14.493 56.208 1.00 60.98 811 CB ILE 629 28.261 13.766 57.423 1.00 65.92 812 CG2 ILE 629 28.292 14.681 58.647 1.00 62.88 813 CG1 ILE 629 27.419 12.536 57.768 1.00 64.60 814 CD1 ILE 629 26.917 11.766 56.571 1.00 63.67 815 C ILE 629 27.852 15.989 56.319 1.00 60.46 816 O ILE 629 28.935 16.452 56.676 1.00 60.38 817 N ASN 630 26.797 16.729 55.994 1.00 61.49 818 CA ASN 630 26.789 18.187 56.015 1.00 61.95 819 CB ASN 630 25.655 18.685 55.149 1.00 60.74 820 CG ASN 630 24.348 18.042 55.516 1.00 63.39 821 OD1 ASN 630 24.011 17.949 56.688 1.00 62.29 822 ND2 ASN 630 23.603 17.591 54.525 1.00 63.08 823 C ASN 630 26.616 18.786 57.402 1.00 63.46 824 O ASN 630 26.311 18.085 58.369 1.00 63.49 825 N GLU 631 26.794 20.103 57.475 1.00 60.97 826 CA GLU 631 26.658 20.840 58.729 1.00 59.85 827 CB GLU 631 26.743 22.349 58.484 1.00 62.90 828 CG GLU 631 26.784 23.166 59.774 1.00 60.34 829 CD GLU 631 25.819 24.340 59.761 1.00 60.36 830 OE1 GLU 631 24.688 24.184 60.288 1.00 62.28 831 OE2 GLU 631 26.191 25.406 59.213 1.00 56.78 832 C GLU 631 25.313 20.519 59.367 1.00 59.95 833 O GLU 631 25.223 20.250 60.564 1.00 61.19 834 N GLN 632 24.268 20.540 58.552 1.00 60.53 835 CA GLN 632 22.933 20.248 59.046 1.00 60.62 836 CB GLN 632 21.930 20.354 57.895 1.00 64.85 837 CG GLN 632 22.121 21.610 57.031 1.00 59.39 838 CD GLN 632 22.081 22.917 57.841 1.00 63.65 839 OE1 GLN 632 21.068 23.248 58.473 1.00 59.92 840 NE2 GLN 632 23.193 23.663 57.821 1.00 62.67 841 C GLN 632 22.873 18.860 59.697 1.00 63.23 842 O GLN 632 22.554 18.741 60.882 1.00 61.37 843 N ARG 633 23.213 17.827 58.929 1.00 62.09 844 CA ARG 633 23.190 16.444 59.406 1.00 61.43 845 CB ARG 633 23.762 15.504 58.345 1.00 60.38 846 CG ARG 633 22.863 15.388 57.142 1.00 58.68 847 CD ARG 633 23.419 14.459 56.102 1.00 63.71 848 NE ARG 633 22.589 14.486 54.905 1.00 62.14 849 CZ ARG 633 22.885 13.852 53.780 1.00 60.28 850 NH1 ARG 633 23.996 13.136 53.704 1.00 60.27 851 NH2 ARG 633 22.075 13.937 52.733 1.00 60.98 852 C ARG 633 23.833 16.137 60.753 1.00 64.07 853 O ARG 633 23.495 15.117 61.348 1.00 60.29 854 N MET 634 24.758 16.970 61.236 1.00 61.53 855 CA MET 634 25.334 16.721 62.560 1.00 60.63 856 CB MET 634 26.429 17.747 62.859 1.00 60.06 857 CG MET 634 27.598 17.688 61.874 1.00 53.30 858 SD MET 634 28.604 16.178 62.057 1.00 63.04 859 CE MET 634 30.133 16.562 61.162 1.00 60.95 860 C MET 634 24.150 16.834 63.555 1.00 60.65 861 O MET 634 23.899 17.897 64.149 1.00 63.14 862 N THR 635 23.420 15.714 63.670 1.00 63.54 863 CA THR 635 22.220 15.523 64.504 1.00 61.73 864 CB THR 635 21.180 14.557 63.819 1.00 59.70 865 OG1 THR 635 20.987 14.911 62.442 1.00 57.94 866 CG2 THR 635 19.829 14.609 64.552 1.00 63.34 867 C THR 635 22.593 14.861 65.825 1.00 61.33 868 O THR 635 23.570 15.251 66.464 1.00 63.49 869 N LEU 636 21.796 13.851 66.198 1.00 60.18 870 CA LEU 636 21.953 13.057 67.420 1.00 61.62 871 CB LEU 636 22.112 11.577 67.095 1.00 60.70 872 CG LEU 636 22.867 10.855 68.213 1.00 62.64 873 CD1 LEU 636 21.904 10.048 69.070 1.00 63.15 874 CD2 LEU 636 23.910 9.960 67.603 1.00 60.79 875 C LEU 636 23.183 13.478 68.172 1.00 61.59 876 O LEU 636 24.287 13.372 67.626 1.00 60.57 877 N PRO 637 23.029 13.907 69.442 1.00 59.83 878 CD PRO 637 22.008 13.402 70.379 1.00 57.71 879 CA PRO 637 24.225 14.321 70.182 1.00 61.11 880 CB PRO 637 23.810 14.133 71.639 1.00 61.28 881 CG PRO 637 22.862 12.966 71.555 1.00 61.68 882 C PRO 637 25.417 13.433 69.793 1.00 61.18 883 O PRO 637 26.457 13.928 69.331 1.00 61.45 884 N CYS 638 25.243 12.117 69.920 1.00 63.53 885 CA CYS 638 26.333 11.211 69.588 1.00 61.78 886 CB CYS 638 26.024 9.787 70.065 1.00 62.20 887 SG CYS 638 24.449 9.498 70.917 1.00 60.82 888 C CYS 638 26.722 11.209 68.101 1.00 61.50 889 O CYS 638 27.863 10.844 67.765 1.00 61.11 890 N MET 639 25.816 11.625 67.214 1.00 57.65 891 CA MET 639 26.186 11.638 65.817 1.00 60.56 892 CB MET 639 25.103 12.211 64.924 1.00 66.32 893 CG MET 639 25.612 12.161 63.532 1.00 60.47 894 SD MET 639 25.084 11.084 62.238 1.00 57.31 895 CE MET 639 25.984 11.962 61.115 1.00 58.45 896 C MET 639 27.478 12.449 65.637 1.00 62.26 897 O MET 639 28.361 12.083 64.857 1.00 61.35 898 N TYR 640 27.589 13.543 66.383 1.00 61.78 899 CA TYR 640 28.797 14.339 66.340 1.00 61.48 900 CB TYR 640 28.569 15.755 66.872 1.00 60.05 901 CG TYR 640 29.871 16.511 66.956 1.00 61.42 902 CD1 TYR 640 30.530 16.927 65.795 1.00 62.42 903 CE1 TYR 640 31.800 17.472 65.846 1.00 61.93 904 CD2 TYR 640 30.519 16.680 68.175 1.00 59.45 905 CE2 TYR 640 31.785 17.222 68.235 1.00 63.13 906 CZ TYR 640 32.425 17.612 67.068 1.00 58.88 907 OH TYR 640 33.711 18.103 67.130 1.00 60.76 908 C TYR 640 29.842 13.646 67.215 1.00 60.30 909 O TYR 640 31.041 13.847 67.034 1.00 63.06 910 N ASP 641 29.397 12.830 68.168 1.00 61.14 911 CA ASP 641 30.349 12.136 69.035 1.00 62.18 912 CB ASP 641 29.674 11.669 70.323 1.00 59.68 913 CG ASP 641 29.145 12.828 71.135 1.00 60.96 914 OD1 ASP 641 27.930 13.090 71.062 1.00 61.07 915 OD2 ASP 641 29.950 13.493 71.824 1.00 63.74 916 C ASP 641 30.991 10.971 68.313 1.00 60.81 917 O ASP 641 32.047 10.482 68.721 1.00 60.52 918 N GLN 642 30.349 10.542 67.229 1.00 59.76 919 CA GLN 642 30.860 9.456 66.396 1.00 63.97 920 CB GLN 642 29.721 8.763 65.687 1.00 61.51 921 CG GLN 642 28.690 8.348 66.642 1.00 61.79 922 CD GLN 642 27.547 7.724 65.978 1.00 62.69 923 OE1 GLN 642 27.709 6.684 65.308 1.00 61.01 924 NE2 GLN 642 26.355 8.326 66.145 1.00 60.03 925 C GLN 642 31.766 10.069 65.359 1.00 62.81 926 O GLN 642 32.954 9.760 65.294 1.00 61.10 927 N CYS 643 31.190 10.957 64.556 1.00 60.88 928 CA CYS 643 31.931 11.628 63.504 1.00 61.65 929 CB CYS 643 30.977 12.508 62.694 1.00 61.95 930 SG CYS 643 29.662 11.585 61.843 1.00 63.26 931 C CYS 643 33.081 12.455 64.071 1.00 61.30 932 O CYS 643 34.102 12.652 63.418 1.00 61.90 933 N LYS 644 32.911 12.923 65.299 1.00 62.82 934 CA LYS 644 33.923 13.730 65.951 1.00 58.73 935 CB LYS 644 33.634 13.827 67.449 1.00 63.83 936 CG LYS 644 34.630 14.686 68.207 1.00 59.96 937 CD LYS 644 34.226 14.891 69.665 1.00 59.57 938 CE LYS 644 35.160 15.902 70.358 1.00 59.22 939 NZ LYS 644 35.201 17.239 69.668 1.00 61.66 940 C LYS 644 35.328 13.182 65.747 1.00 61.72 941 O LYS 644 36.296 13.941 65.673 1.00 61.77 942 N HIS 645 35.451 11.864 65.655 1.00 61.41 943 CA HIS 645 36.769 11.262 65.474 1.00 59.96 944 CB HIS 645 36.856 9.943 66.209 1.00 60.26 945 CG HIS 645 37.109 10.100 67.667 1.00 59.75 946 CD2 HIS 645 38.254 10.338 68.346 1.00 58.42 947 ND1 HIS 645 36.103 10.041 68.606 1.00 61.77 948 CE1 HIS 645 36.621 10.232 69.805 1.00 58.75 949 NE2 HIS 645 37.924 10.415 69.675 1.00 57.48 950 C HIS 645 37.165 11.038 64.037 1.00 60.84 951 O HIS 645 38.352 11.000 63.727 1.00 62.12 952 N MET 646 36.172 10.856 63.174 1.00 63.11 953 CA MET 646 36.432 10.651 61.759 1.00 62.74 954 CB MET 646 35.135 10.211 61.023 1.00 61.50 955 CG MET 646 34.686 8.771 61.338 1.00 58.88 956 SD MET 646 32.994 8.315 60.876 1.00 61.92 957 CE MET 646 32.426 8.134 62.441 1.00 62.24 958 C MET 646 36.948 11.972 61.168 1.00 63.61 959 O MET 646 37.709 11.962 60.197 1.00 63.12 960 N LEU 647 36.543 13.093 61.772 1.00 60.39 961 CA LEU 647 36.963 14.419 61.325 1.00 61.16 962 CB LEU 647 36.105 15.510 61.965 1.00 62.09 963 CG LEU 647 34.661 15.778 61.551 1.00 62.69 964 CD1 LEU 647 34.144 16.850 62.479 1.00 59.66 965 CD2 LEU 647 34.553 16.232 60.098 1.00 61.60 966 C LEU 647 38.400 14.652 61.731 1.00 62.99 967 O LEU 647 39.164 15.329 61.042 1.00 62.41 968 N TYR 648 38.750 14.087 62.876 1.00 60.24 969 CA TYR 648 40.087 14.202 63.431 1.00 60.92 970 CB TYR 648 40.190 13.339 64.685 1.00 59.63 971 CG TYR 648 41.486 13.510 65.428 1.00 60.33 972 CD1 TYR 648 42.672 12.950 64.952 1.00 62.96 973 CE1 TYR 648 43.876 13.160 65.609 1.00 61.51 974 CD2 TYR 648 41.537 14.280 66.585 1.00 57.67 975 CE2 TYR 648 42.735 14.500 67.252 1.00 62.62 976 CZ TYR 648 43.902 13.938 66.759 1.00 60.16 977 OH TYR 648 45.089 14.157 67.426 1.00 64.40 978 C TYR 648 41.164 13.787 62.435 1.00 61.32 979 O TYR 648 42.045 14.575 62.099 1.00 62.83 980 N VAL 649 41.107 12.545 61.971 1.00 65.90 981 CA VAL 649 42.105 12.079 61.027 1.00 60.14 982 CB VAL 649 41.862 10.578 60.642 1.00 59.02 983 CG1 VAL 649 40.528 10.109 61.218 1.00 60.92 984 CG2 VAL 649 41.930 10.372 59.122 1.00 59.70 985 C VAL 649 42.072 12.982 59.814 1.00 61.99 986 O VAL 649 43.105 13.378 59.297 1.00 60.55 987 N SER 650 40.873 13.339 59.390 1.00 61.60 988 CA SER 650 40.705 14.191 58.226 1.00 61.66 989 CB SER 650 39.224 14.356 57.914 1.00 61.34 990 OG SER 650 39.069 14.979 56.662 1.00 64.56 991 C SER 650 41.344 15.555 58.429 1.00 61.44 992 O SER 650 41.800 16.181 57.476 1.00 58.88 993 N SER 651 41.365 16.013 59.677 1.00 59.26 994 CA SER 651 41.960 17.298 60.029 1.00 62.47 995 CB SER 651 41.578 17.637 61.483 1.00 58.62 996 OG SER 651 42.537 18.441 62.154 1.00 60.41 997 C SER 651 43.480 17.204 59.849 1.00 61.76 998 O SER 651 44.087 18.019 59.164 1.00 62.09 999 N GLU 652 44.070 16.172 60.441 1.00 60.41 1000 CA GLU 652 45.509 15.927 60.395 1.00 60.48 1001 CB GLU 652 45.837 14.680 61.220 1.00 65.10 1002 CG GLU 652 45.488 14.822 62.677 1.00 59.36 1003 CD GLU 652 46.160 16.021 63.289 1.00 62.29 1004 OE1 GLU 652 47.399 15.970 63.444 1.00 60.10 1005 OE2 GLU 652 45.451 17.014 63.592 1.00 60.61 1006 C GLU 652 46.100 15.773 59.001 1.00 59.16 1007 O GLU 652 47.238 16.166 58.755 1.00 59.92 1008 N LEU 653 45.335 15.180 58.094 1.00 60.01 1009 CA LEU 653 45.807 14.984 56.731 1.00 61.61 1010 CB LEU 653 44.874 14.048 55.960 1.00 64.78 1011 CG LEU 653 44.860 12.600 56.432 1.00 63.03 1012 CD1 LEU 653 43.723 11.868 55.768 1.00 60.96 1013 CD2 LEU 653 46.179 11.941 56.122 1.00 62.70 1014 C LEU 653 45.878 16.328 56.037 1.00 60.72 1015 O LEU 653 46.805 16.588 55.269 1.00 61.12 1016 N HIS 654 44.895 17.182 56.303 1.00 62.78 1017 CA HIS 654 44.894 18.497 55.698 1.00 61.32 1018 CB HIS 654 43.513 19.141 55.805 1.00 63.28 1019 CG HIS 654 43.517 20.607 55.518 1.00 61.88 1020 CD2 HIS 654 43.210 21.296 54.394 1.00 59.76 1021 ND1 HIS 654 43.946 21.543 56.436 1.00 58.15 1022 CE1 HIS 654 43.905 22.744 55.889 1.00 62.74 1023 NE2 HIS 654 43.463 22.622 54.650 1.00 60.79 1024 C HIS 654 45.935 19.319 56.440 1.00 62.39 1025 O HIS 654 46.667 20.112 55.851 1.00 62.10 1026 N ARG 655 46.012 19.098 57.743 1.00 62.07 1027 CA ARG 655 46.968 19.804 58.572 1.00 62.85 1028 CB ARG 655 46.882 19.277 60.008 1.00 58.45 1029 CG ARG 655 47.082 20.314 61.111 1.00 57.53 1030 CD ARG 655 48.522 20.368 61.565 1.00 58.48 1031 NE ARG 655 48.968 19.079 62.082 1.00 61.43 1032 CZ ARG 655 50.206 18.831 62.503 1.00 59.99 1033 NH1 ARG 655 51.125 19.790 62.472 1.00 61.84 1034 NH2 ARG 655 50.537 17.625 62.950 1.00 60.75 1035 C ARG 655 48.367 19.599 57.999 1.00 60.66 1036 O ARG 655 49.086 20.566 57.753 1.00 62.69 1037 N LEU 656 48.735 18.340 57.759 1.00 60.05 1038 CA LEU 656 50.060 18.008 57.224 1.00 61.69 1039 CB LEU 656 50.575 16.697 57.832 1.00 60.63 1040 CG LEU 656 50.902 16.651 59.330 1.00 60.12 1041 CD1 LEU 656 51.059 15.205 59.759 1.00 61.83 1042 CD2 LEU 656 52.161 17.440 59.632 1.00 61.33 1043 C LEU 656 50.164 17.922 55.706 1.00 60.82 1044 O LEU 656 51.187 17.491 55.184 1.00 63.77 1045 N GLN 657 49.119 18.321 54.995 1.00 62.25 1046 CA GLN 657 49.165 18.291 53.543 1.00 62.13 1047 CB GLN 657 50.018 19.442 53.026 1.00 59.95 1048 CG GLN 657 49.412 20.805 53.219 1.00 60.54 1049 CD GLN 657 48.109 20.944 52.480 1.00 59.94 1050 OE1 GLN 657 47.043 20.616 52.997 1.00 61.59 1051 NE2 GLN 657 48.189 21.413 51.250 1.00 59.69 1052 C GLN 657 49.756 16.998 53.027 1.00 64.37 1053 O GLN 657 50.684 17.013 52.230 1.00 60.80 1054 N VAL 658 49.233 15.876 53.487 1.00 59.26 1055 CA VAL 658 49.730 14.589 53.048 1.00 60.79 1056 CB VAL 658 49.044 13.466 53.856 1.00 61.35 1057 CG1 VAL 658 49.169 12.130 53.154 1.00 61.79 1058 CG2 VAL 658 49.663 13.406 55.240 1.00 61.37 1059 C VAL 658 49.494 14.416 51.552 1.00 60.15 1060 O VAL 658 48.452 14.798 51.025 1.00 60.95 1061 N SER 659 50.485 13.862 50.869 1.00 63.41 1062 CA SER 659 50.399 13.615 49.438 1.00 58.10 1063 CB SER 659 51.797 13.685 48.834 1.00 59.86 1064 OG SER 659 52.018 12.643 47.905 1.00 62.03 1065 C SER 659 49.777 12.242 49.157 1.00 62.11 1066 O SER 659 49.781 11.353 50.015 1.00 61.38 1067 N TYR 660 49.243 12.062 47.956 1.00 60.30 1068 CA TYR 660 48.633 10.789 47.601 1.00 61.68 1069 CB TYR 660 48.100 10.860 46.177 1.00 61.85 1070 CG TYR 660 47.411 9.605 45.727 1.00 59.67 1071 CD1 TYR 660 46.561 8.911 46.581 1.00 63.51 1072 CE1 TYR 660 45.893 7.783 46.152 1.00 60.60 1073 CD2 TYR 660 47.576 9.134 44.431 1.00 60.37 1074 CE2 TYR 660 46.911 8.011 43.990 1.00 64.13 1075 CZ TYR 660 46.072 7.339 44.851 1.00 63.85 1076 OH TYR 660 45.393 6.229 44.402 1.00 62.07 1077 C TYR 660 49.584 9.594 47.749 1.00 59.81 1078 O TYR 660 49.175 8.510 48.165 1.00 64.86 1079 N GLU 661 50.853 9.789 47.411 1.00 60.25 1080 CA GLU 661 51.814 8.703 47.527 1.00 62.48 1081 CB GLU 661 53.119 9.034 46.788 1.00 61.23 1082 CG GLU 661 53.209 8.405 45.395 1.00 63.67 1083 CD GLU 661 54.517 8.708 44.672 1.00 65.78 1084 OE1 GLU 661 55.602 8.472 45.247 1.00 60.21 1085 OE2 GLU 661 54.462 9.174 43.517 1.00 60.28 1086 C GLU 661 52.096 8.354 48.980 1.00 61.69 1087 O GLU 661 52.247 7.183 49.312 1.00 61.32 1088 N GLU 662 52.160 9.348 49.854 1.00 62.68 1089 CA GLU 662 52.405 9.048 51.252 1.00 63.61 1090 CB GLU 662 52.605 10.340 52.032 1.00 61.04 1091 CG GLU 662 53.485 11.321 51.309 1.00 61.12 1092 CD GLU 662 53.768 12.555 52.117 1.00 62.85 1093 OE1 GLU 662 52.822 13.164 52.637 1.00 58.86 1094 OE2 GLU 662 54.945 12.931 52.227 1.00 61.02 1095 C GLU 662 51.193 8.277 51.784 1.00 59.86 1096 O GLU 662 51.333 7.263 52.466 1.00 63.08 1097 N TYR 663 50.007 8.771 51.436 1.00 61.62 1098 CA TYR 663 48.716 8.186 51.812 1.00 62.54 1099 CB TYR 663 47.601 8.921 51.068 1.00 63.89 1100 CG TYR 663 46.266 8.230 51.167 1.00 61.84 1101 CD1 TYR 663 45.619 8.109 52.392 1.00 59.60 1102 CE1 TYR 663 44.407 7.458 52.498 1.00 58.52 1103 CD2 TYR 663 45.659 7.676 50.043 1.00 58.65 1104 CE2 TYR 663 44.441 7.019 50.138 1.00 60.83 1105 CZ TYR 663 43.820 6.916 51.368 1.00 62.58 1106 OH TYR 663 42.601 6.287 51.477 1.00 61.21 1107 C TYR 663 48.565 6.680 51.537 1.00 59.94 1108 O TYR 663 48.090 5.918 52.389 1.00 60.92 1109 N LEU 664 48.930 6.274 50.325 1.00 60.84 1110 CA LEU 664 48.846 4.881 49.908 1.00 61.56 1111 CB LEU 664 49.261 4.757 48.438 1.00 60.37 1112 CG LEU 664 48.363 5.402 47.382 1.00 64.33 1113 CD1 LEU 664 49.036 5.350 46.023 1.00 64.49 1114 CD2 LEU 664 47.032 4.687 47.351 1.00 59.02 1115 C LEU 664 49.744 4.001 50.777 1.00 60.21 1116 O LEU 664 49.369 2.889 51.161 1.00 61.89 1117 N CYS 665 50.933 4.519 51.071 1.00 61.72 1118 CA CYS 665 51.915 3.823 51.882 1.00 58.12 1119 CB CYS 665 53.272 4.508 51.737 1.00 62.31 1120 SG CYS 665 54.006 4.295 50.123 1.00 59.12 1121 C CYS 665 51.516 3.771 53.348 1.00 59.84 1122 O CYS 665 51.726 2.766 54.024 1.00 61.71 1123 N MET 666 50.953 4.862 53.845 1.00 63.34 1124 CA MET 666 50.524 4.910 55.228 1.00 58.59 1125 CB MET 666 50.199 6.341 55.627 1.00 59.71 1126 CG MET 666 51.408 7.189 55.867 1.00 62.55 1127 SD MET 666 50.921 8.891 56.036 1.00 61.95 1128 CE MET 666 50.313 8.927 57.659 1.00 64.15 1129 C MET 666 49.303 4.023 55.437 1.00 63.86 1130 O MET 666 49.146 3.420 56.495 1.00 59.48 1131 N LYS 667 48.446 3.950 54.421 1.00 58.08 1132 CA LYS 667 47.241 3.129 54.482 1.00 61.17 1133 CB LYS 667 46.318 3.429 53.305 1.00 66.33 1134 CG LYS 667 45.013 2.663 53.338 1.00 59.73 1135 CD LYS 667 43.951 3.382 52.532 1.00 60.07 1136 CE LYS 667 44.313 3.462 51.063 1.00 62.82 1137 NZ LYS 667 44.134 2.158 50.390 1.00 62.44 1138 C LYS 667 47.592 1.658 54.468 1.00 63.84 1139 O LYS 667 46.867 0.838 55.011 1.00 61.95 1140 N THR 668 48.705 1.318 53.838 1.00 63.32 1141 CA THR 668 49.114 −0.069 53.801 1.00 61.88 1142 CB THR 668 50.080 −0.304 52.657 1.00 60.27 1143 OG1 THR 668 49.463 0.124 51.439 1.00 62.16 1144 CG2 THR 668 50.417 −1.775 52.547 1.00 58.76 1145 C THR 668 49.761 −0.413 55.137 1.00 62.68 1146 O THR 668 49.707 −1.559 55.591 1.00 62.61 1147 N LEU 669 50.350 0.597 55.773 1.00 62.26 1148 CA LEU 669 50.995 0.427 57.068 1.00 61.58 1149 CB LEU 669 51.888 1.626 57.378 1.00 62.50 1150 CG LEU 669 53.265 1.643 56.712 1.00 57.56 1151 CD1 LEU 669 54.041 2.847 57.205 1.00 60.97 1152 CD2 LEU 669 54.012 0.355 57.037 1.00 59.22 1153 C LEU 669 49.987 0.249 58.194 1.00 61.00 1154 O LEU 669 50.354 −0.119 59.310 1.00 61.30 1155 N LEU 670 48.718 0.520 57.911 1.00 62.31 1156 CA LEU 670 47.686 0.365 58.925 1.00 62.17 1157 CB LEU 670 46.511 1.305 58.638 1.00 64.37 1158 CG LEU 670 46.784 2.784 58.942 1.00 60.87 1159 CD1 LEU 670 45.516 3.597 58.766 1.00 63.22 1160 CD2 LEU 670 47.293 2.922 60.365 1.00 58.85 1161 C LEU 670 47.227 −1.090 58.976 1.00 63.40 1162 O LEU 670 46.846 −1.599 60.026 1.00 63.58 1163 N LEU 671 47.281 −1.750 57.827 1.00 61.89 1164 CA LEU 671 46.913 −3.150 57.716 1.00 60.74 1165 CB LEU 671 46.946 −3.574 56.249 1.00 62.54 1166 CG LEU 671 46.501 −4.997 55.921 1.00 62.48 1167 CD1 LEU 671 45.015 −5.180 56.251 1.00 63.63 1168 CD2 LEU 671 46.768 −5.260 54.449 1.00 63.52 1169 C LEU 671 47.967 −3.928 58.500 1.00 61.46 1170 O LEU 671 47.688 −4.971 59.110 1.00 60.81 1171 N LEU 672 49.182 −3.388 58.479 1.00 62.75 1172 CA LEU 672 50.320 −3.974 59.163 1.00 62.92 1173 CB LEU 672 51.562 −3.883 58.280 1.00 60.56 1174 CG LEU 672 51.399 −4.164 56.786 1.00 62.90 1175 CD1 LEU 672 52.776 −4.394 56.183 1.00 60.90 1176 CD2 LEU 672 50.519 −5.373 56.558 1.00 61.77 1177 C LEU 672 50.576 −3.232 60.468 1.00 61.14 1178 O LEU 672 51.722 −3.064 60.883 1.00 63.28 1179 N SER 673 49.502 −2.795 61.116 1.00 62.86 1180 CA SER 673 49.616 −2.056 62.368 1.00 62.27 1181 CB SER 673 48.582 −0.910 62.405 1.00 61.42 1182 OG SER 673 47.241 −1.383 62.404 1.00 59.49 1183 C SER 673 49.468 −2.925 63.616 1.00 63.23 1184 O SER 673 50.026 −2.608 64.664 1.00 59.71 1185 N SER 674 48.720 −4.017 63.517 1.00 61.92 1186 CA SER 674 48.538 −4.875 64.680 1.00 60.38 1187 CB SER 674 47.225 −4.506 65.401 1.00 62.70 1188 OG SER 674 46.204 −4.115 64.495 1.00 56.91 1189 C SER 674 48.590 −6.373 64.405 1.00 61.52 1190 O SER 674 48.122 −6.849 63.377 1.00 61.47 1191 N VAL 675 49.192 −7.101 65.336 1.00 64.16 1192 CA VAL 675 49.305 −8.556 65.256 1.00 61.09 1193 CB VAL 675 50.722 −9.025 64.816 1.00 62.88 1194 CG1 VAL 675 50.962 −8.679 63.362 1.00 59.26 1195 CG2 VAL 675 51.787 −8.394 65.710 1.00 61.45 1196 C VAL 675 49.039 −9.116 66.652 1.00 62.60 1197 O VAL 675 49.265 −8.433 67.656 1.00 61.24 1198 N PRO 676 48.550 −10.363 66.735 1.00 59.77 1199 CD PRO 676 48.219 −11.265 65.616 1.00 57.51 1200 CA PRO 676 48.260 −11.001 68.020 1.00 62.72 1201 CB PRO 676 48.026 −12.452 67.623 1.00 60.61 1202 CG PRO 676 47.362 −12.317 66.283 1.00 59.30 1203 C PRO 676 49.424 −10.847 68.994 1.00 61.35 1204 O PRO 676 50.585 −10.758 68.576 1.00 63.84 1205 N LYS 677 49.117 −10.818 70.290 1.00 62.54 1206 CA LYS 677 50.154 −10.673 71.314 1.00 60.54 1207 CB LYS 677 49.510 −10.646 72.702 1.00 61.63 1208 CG LYS 677 50.472 −10.433 73.853 1.00 58.65 1209 CD LYS 677 49.861 −10.969 75.143 1.00 62.01 1210 CE LYS 677 50.912 −11.109 76.241 1.00 63.79 1211 NZ LYS 677 50.350 −11.727 77.491 1.00 60.49 1212 C LYS 677 51.162 −11.828 71.222 1.00 61.45 1213 O LYS 677 52.102 −11.917 72.023 1.00 59.62 1214 N ASP 678 50.955 −12.698 70.231 1.00 59.93 1215 CA ASP 678 51.809 −13.862 69.994 1.00 60.14 1216 CB ASP 678 51.041 −15.126 70.367 1.00 60.09 1217 CG ASP 678 50.390 −15.023 71.735 1.00 61.43 1218 OD1 ASP 678 51.110 −14.940 72.749 1.00 62.42 1219 OD2 ASP 678 49.151 −15.016 71.797 1.00 60.77 1220 C ASP 678 52.273 −13.947 68.535 1.00 63.29 1221 O ASP 678 52.771 −14.981 68.090 1.00 59.36 1222 N GLY 679 52.098 −12.854 67.797 1.00 59.82 1223 CA GLY 679 52.512 −12.823 66.408 1.00 58.14 1224 C GLY 679 51.639 −13.640 65.481 1.00 58.50 1225 O GLY 679 50.600 −14.179 65.870 1.00 58.88 1226 N LEU 680 52.082 −13.723 64.237 1.00 62.95 1227 CA LEU 680 51.375 −14.459 63.209 1.00 63.18 1228 CB LEU 680 51.233 −13.564 61.981 1.00 65.44 1229 CG LEU 680 50.941 −12.101 62.324 1.00 60.24 1230 CD1 LEU 680 50.994 −11.260 61.069 1.00 60.21 1231 CD2 LEU 680 49.582 −11.979 62.974 1.00 60.11 1232 C LEU 680 52.221 −15.685 62.881 1.00 63.74 1233 O LEU 680 53.430 −15.689 63.110 1.00 62.10 1234 N LYS 681 51.598 −16.729 62.354 1.00 60.36 1235 CA LYS 681 52.348 −17.922 62.000 1.00 60.78 1236 CB LYS 681 51.406 −18.969 61.418 1.00 60.11 1237 CG LYS 681 50.209 −19.253 62.289 1.00 61.43 1238 CD LYS 681 49.295 −20.221 61.579 1.00 63.30 1239 CE LYS 681 47.908 −20.186 62.160 1.00 61.77 1240 NZ LYS 681 46.983 −20.886 61.244 1.00 62.13 1241 C LYS 681 53.429 −17.551 60.973 1.00 61.58 1242 O LYS 681 54.401 −18.286 60.784 1.00 63.01 1243 N SER 682 53.250 −16.410 60.309 1.00 60.35 1244 CA SER 682 54.211 −15.932 59.314 1.00 62.36 1245 CB SER 682 53.515 −15.613 57.989 1.00 61.24 1246 OG SER 682 53.066 −16.788 57.346 1.00 63.18 1247 C SER 682 54.885 −14.674 59.826 1.00 64.68 1248 O SER 682 55.289 −13.814 59.051 1.00 59.53 1249 N GLN 683 55.012 −14.579 61.140 1.00 64.92 1250 CA GLN 683 55.614 −13.411 61.754 1.00 62.89 1251 CB GLN 683 55.862 −13.679 63.240 1.00 63.65 1252 CG GLN 683 56.282 −12.452 64.059 1.00 64.38 1253 CD GLN 683 55.318 −11.274 63.954 1.00 64.26 1254 OE1 GLN 683 55.688 −10.205 63.476 1.00 63.72 1255 NE2 GLN 683 54.085 −11.465 64.407 1.00 61.52 1256 C GLN 683 56.893 −12.938 61.069 1.00 60.69 1257 O GLN 683 56.981 −11.782 60.669 1.00 62.35 1258 N GLU 684 57.880 −13.811 60.913 1.00 60.59 1259 CA GLU 684 59.119 −13.378 60.279 1.00 61.72 1260 CB GLU 684 60.039 −14.567 59.970 1.00 61.83 1261 CG GLU 684 60.015 −15.013 58.511 1.00 61.93 1262 CD GLU 684 61.383 −15.418 57.979 1.00 60.75 1263 OE1 GLU 684 61.457 −15.813 56.792 1.00 60.52 1264 OE2 GLU 684 62.375 −15.342 58.744 1.00 58.72 1265 C GLU 684 58.801 −12.623 58.993 1.00 60.55 1266 O GLU 684 59.196 −11.474 58.823 1.00 63.55 1267 N LEU 685 58.064 −13.263 58.100 1.00 63.64 1268 CA LEU 685 57.710 −12.649 56.834 1.00 57.80 1269 CB LEU 685 56.921 −13.649 55.985 1.00 59.68 1270 CG LEU 685 57.165 −13.734 54.476 1.00 63.20 1271 CD1 LEU 685 55.839 −14.063 53.829 1.00 59.43 1272 CD2 LEU 685 57.699 −12.434 53.902 1.00 62.25 1273 C LEU 685 56.882 −11.370 57.040 1.00 62.31 1274 O LEU 685 56.953 −10.432 56.242 1.00 61.77 1275 N PHE 686 56.095 −11.326 58.109 1.00 60.23 1276 CA PHE 686 55.272 −10.149 58.374 1.00 61.37 1277 CB PHE 686 54.409 −10.365 59.609 1.00 64.14 1278 CG PHE 686 53.663 −9.143 60.023 1.00 61.62 1279 CD1 PHE 686 52.639 −8.650 59.236 1.00 60.24 1280 CD2 PHE 686 54.008 −8.460 61.178 1.00 62.13 1281 CE1 PHE 686 51.971 −7.493 59.592 1.00 58.68 1282 CE2 PHE 686 53.347 −7.304 61.543 1.00 61.95 1283 CZ PHE 686 52.326 −6.818 60.749 1.00 61.43 1284 C PHE 686 56.109 −8.897 58.596 1.00 59.14 1285 O PHE 686 56.247 −8.051 57.714 1.00 61.44 1286 N ASP 687 56.651 −8.791 59.802 1.00 64.05 1287 CA ASP 687 57.483 −7.668 60.195 1.00 60.85 1288 CB ASP 687 58.102 −7.960 61.567 1.00 56.84 1289 CG ASP 687 59.033 −9.162 61.536 1.00 64.67 1290 OD1 ASP 687 59.482 −9.610 62.622 1.00 60.21 1291 OD2 ASP 687 59.322 −9.655 60.414 1.00 63.02 1292 C ASP 687 58.573 −7.383 59.142 1.00 61.59 1293 O ASP 687 59.262 −6.358 59.214 1.00 61.60 1294 N GLU 688 58.725 −8.289 58.172 1.00 60.82 1295 CA GLU 688 59.700 −8.104 57.098 1.00 59.68 1296 CB GLU 688 60.246 −9.433 56.604 1.00 62.54 1297 CG GLU 688 61.434 −9.252 55.674 1.00 60.98 1298 CD GLU 688 61.479 −10.289 54.569 1.00 58.58 1299 OE1 GLU 688 61.323 −9.898 53.387 1.00 61.73 1300 OE2 GLU 688 61.663 −11.490 54.882 1.00 60.24 1301 C GLU 688 59.031 −7.387 55.931 1.00 60.97 1302 O GLU 688 59.684 −6.719 55.137 1.00 62.27 1303 N ILE 689 57.721 −7.552 55.809 1.00 61.23 1304 CA ILE 689 56.979 −6.864 54.767 1.00 61.00 1305 CB ILE 689 55.641 −7.592 54.451 1.00 63.41 1306 CG2 ILE 689 54.655 −6.650 53.759 1.00 59.25 1307 CG1 ILE 689 55.916 −8.808 53.568 1.00 57.54 1308 CD1 ILE 689 54.667 −9.526 53.121 1.00 62.29 1309 C ILE 689 56.704 −5.479 55.345 1.00 58.97 1310 O ILE 689 56.778 −4.473 54.645 1.00 61.54 1311 N ARG 690 56.411 −5.439 56.641 1.00 60.16 1312 CA ARG 690 56.135 −4.185 57.319 1.00 61.28 1313 CB ARG 690 55.855 −4.434 58.799 1.00 60.29 1314 CG ARG 690 55.548 −3.170 59.582 1.00 60.74 1315 CD ARG 690 54.679 −3.480 60.770 1.00 56.91 1316 NE ARG 690 54.190 −2.280 61.437 1.00 66.99 1317 CZ ARG 690 54.967 −1.378 62.026 1.00 64.04 1318 NH1 ARG 690 56.283 −1.533 62.029 1.00 58.19 1319 NH2 ARG 690 54.427 −0.327 62.623 1.00 62.52 1320 C ARG 690 57.274 −3.179 57.177 1.00 57.93 1321 O ARG 690 57.037 −1.977 57.067 1.00 59.25 1322 N MET 691 58.512 −3.660 57.190 1.00 58.75 1323 CA MET 691 59.664 −2.783 57.048 1.00 64.96 1324 CB MET 691 60.928 −3.542 57.450 1.00 61.53 1325 CG MET 691 62.247 −3.016 56.886 1.00 59.40 1326 SD MET 691 62.942 −4.201 55.673 1.00 61.45 1327 CE MET 691 63.225 −5.669 56.764 1.00 60.93 1328 C MET 691 59.775 −2.254 55.621 1.00 61.68 1329 O MET 691 60.130 −1.099 55.405 1.00 63.95 1330 N THR 692 59.459 −3.097 54.646 1.00 59.70 1331 CA THR 692 59.519 −2.698 53.243 1.00 60.57 1332 CB THR 692 59.105 −3.855 52.323 1.00 62.51 1333 OG1 THR 692 59.796 −5.046 52.714 1.00 59.90 1334 CG2 THR 692 59.437 −3.523 50.879 1.00 60.93 1335 C THR 692 58.586 −1.523 52.962 1.00 60.46 1336 O THR 692 58.890 −0.655 52.143 1.00 59.04 1337 N TYR 693 57.439 −1.516 53.634 1.00 61.66 1338 CA TYR 693 56.459 −0.458 53.461 1.00 60.32 1339 CB TYR 693 55.045 −1.033 53.553 1.00 59.81 1340 CG TYR 693 54.665 −1.802 52.302 1.00 61.04 1341 CD1 TYR 693 54.552 −1.153 51.073 1.00 63.46 1342 CE1 TYR 693 54.292 −1.865 49.909 1.00 65.96 1343 CD2 TYR 693 54.497 −3.185 52.332 1.00 59.82 1344 CE2 TYR 693 54.236 −3.906 51.170 1.00 63.54 1345 CZ TYR 693 54.137 −3.242 49.967 1.00 62.96 1346 OH TYR 693 53.901 −3.961 48.822 1.00 59.68 1347 C TYR 693 56.663 0.664 54.458 1.00 58.94 1348 O TYR 693 55.877 1.600 54.527 1.00 59.49 1349 N ILE 694 57.720 0.555 55.248 1.00 63.16 1350 CA ILE 694 58.052 1.598 56.195 1.00 61.35 1351 CB ILE 694 58.734 1.042 57.462 1.00 59.89 1352 CG2 ILE 694 59.652 2.101 58.077 1.00 62.13 1353 CG1 ILE 694 57.668 0.580 58.457 1.00 63.95 1354 CD1 ILE 694 58.216 0.168 59.793 1.00 61.57 1355 C ILE 694 59.028 2.478 55.430 1.00 58.86 1356 O ILE 694 58.989 3.701 55.541 1.00 62.76 1357 N LYS 695 59.890 1.838 54.643 1.00 61.80 1358 CA LYS 695 60.869 2.539 53.821 1.00 60.19 1359 CB LYS 695 61.987 1.607 53.364 1.00 61.05 1360 CG LYS 695 62.768 0.892 54.438 1.00 60.54 1361 CD LYS 695 63.876 0.081 53.767 1.00 63.44 1362 CE LYS 695 64.516 −0.947 54.699 1.00 61.61 1363 NZ LYS 695 65.330 −1.962 53.942 1.00 62.18 1364 C LYS 695 60.206 3.074 52.559 1.00 61.44 1365 O LYS 695 60.706 4.010 51.946 1.00 61.23 1366 N GLU 696 59.101 2.452 52.156 1.00 61.65 1367 CA GLU 696 58.381 2.862 50.961 1.00 60.70 1368 CB GLU 696 57.289 1.851 50.635 1.00 62.74 1369 CG GLU 696 56.806 1.901 49.200 1.00 63.74 1370 CD GLU 696 57.927 1.725 48.187 1.00 63.24 1371 OE1 GLU 696 58.903 1.002 48.494 1.00 61.23 1372 OE2 GLU 696 57.824 2.299 47.079 1.00 62.98 1373 C GLU 696 57.775 4.215 51.260 1.00 61.27 1374 O GLU 696 57.594 5.051 50.366 1.00 61.63 1375 N LEU 697 57.468 4.414 52.540 1.00 59.99 1376 CA LEU 697 56.912 5.668 53.022 1.00 63.89 1377 CB LEU 697 56.314 5.493 54.418 1.00 58.18 1378 CG LEU 697 55.831 6.810 55.016 1.00 62.97 1379 CD1 LEU 697 54.754 7.370 54.127 1.00 59.80 1380 CD2 LEU 697 55.319 6.606 56.425 1.00 59.24 1381 C LEU 697 58.029 6.709 53.072 1.00 61.66 1382 O LEU 697 57.807 7.871 52.774 1.00 60.35 1383 N GLY 698 59.228 6.283 53.460 1.00 59.57 1384 CA GLY 698 60.348 7.198 53.523 1.00 61.15 1385 C GLY 698 60.570 7.770 52.146 1.00 60.91 1386 O GLY 698 60.748 8.977 51.988 1.00 61.15 1387 N LYS 699 60.557 6.880 51.156 1.00 60.97 1388 CA LYS 699 60.729 7.219 49.745 1.00 60.90 1389 CB LYS 699 60.526 5.983 48.875 1.00 66.06 1390 CG LYS 699 61.729 5.098 48.621 1.00 61.25 1391 CD LYS 699 61.290 3.930 47.737 1.00 59.41 1392 CE LYS 699 62.371 3.498 46.765 1.00 61.62 1393 NZ LYS 699 63.066 2.246 47.178 1.00 60.87 1394 C LYS 699 59.710 8.256 49.289 1.00 58.54 1395 O LYS 699 60.019 9.127 48.482 1.00 59.98 1396 N ALA 700 58.483 8.128 49.777 1.00 63.02 1397 CA ALA 700 57.423 9.048 49.408 1.00 61.82 1398 CB ALA 700 56.094 8.540 49.926 1.00 65.26 1399 C ALA 700 57.712 10.422 49.977 1.00 60.36 1400 O ALA 700 57.545 11.434 49.298 1.00 62.77 1401 N ILE 701 58.137 10.446 51.235 1.00 65.16 1402 CA ILE 701 58.471 11.683 51.917 1.00 64.84 1403 CB ILE 701 58.931 11.406 53.338 1.00 61.36 1404 CG2 ILE 701 59.509 12.670 53.953 1.00 63.03 1405 CG1 ILE 701 57.761 10.874 54.151 1.00 61.61 1406 CD1 ILE 701 58.167 10.364 55.495 1.00 60.05 1407 C ILE 701 59.574 12.455 51.195 1.00 61.64 1408 O ILE 701 59.597 13.683 51.228 1.00 58.62 1409 N VAL 702 60.500 11.749 50.555 1.00 63.95 1410 CA VAL 702 61.560 12.438 49.831 1.00 57.69 1411 CB VAL 702 62.815 11.532 49.665 1.00 63.59 1412 CG1 VAL 702 63.310 11.093 51.024 1.00 59.75 1413 CG2 VAL 702 62.494 10.330 48.819 1.00 64.22 1414 C VAL 702 61.038 12.907 48.466 1.00 61.62 1415 O VAL 702 61.328 14.014 48.031 1.00 61.64 1416 N LYS 703 60.244 12.065 47.814 1.00 61.58 1417 CA LYS 703 59.666 12.387 46.516 1.00 60.75 1418 CB LYS 703 58.475 11.474 46.201 1.00 56.80 1419 CG LYS 703 57.419 12.161 45.293 1.00 59.93 1420 CD LYS 703 55.967 11.815 45.660 1.00 60.60 1421 CE LYS 703 54.962 12.848 45.088 1.00 57.15 1422 NZ LYS 703 55.070 13.064 43.605 1.00 62.62 1423 C LYS 703 59.169 13.814 46.392 1.00 61.49 1424 O LYS 703 59.454 14.472 45.404 1.00 58.34 1425 N ARG 704 58.390 14.271 47.367 1.00 63.00 1426 CA ARG 704 57.826 15.621 47.321 1.00 60.60 1427 CB ARG 704 56.331 15.590 47.661 1.00 62.95 1428 CG ARG 704 56.026 15.010 49.033 1.00 61.71 1429 CD ARG 704 54.728 15.553 49.548 1.00 60.30 1430 NE ARG 704 54.931 16.417 50.702 1.00 62.33 1431 CZ ARG 704 53.983 17.200 51.204 1.00 60.19 1432 NH1 ARG 704 52.784 17.213 50.640 1.00 61.68 1433 NH2 ARG 704 54.225 17.965 52.263 1.00 63.26 1434 C ARG 704 58.520 16.607 48.249 1.00 63.14 1435 O ARG 704 58.732 17.772 47.885 1.00 60.41 1436 N GLU 705 58.842 16.155 49.458 1.00 60.89 1437 CA GLU 705 59.528 17.018 50.412 1.00 62.58 1438 CB GLU 705 59.814 16.288 51.730 1.00 60.91 1439 CG GLU 705 58.605 16.091 52.605 1.00 62.30 1440 CD GLU 705 57.847 17.384 52.817 1.00 64.22 1441 OE1 GLU 705 56.684 17.460 52.347 1.00 58.55 1442 OE2 GLU 705 58.419 18.317 53.440 1.00 61.42 1443 C GLU 705 60.848 17.456 49.801 1.00 62.10 1444 O GLU 705 61.869 16.761 49.939 1.00 59.78 1445 N GLY 706 60.823 18.597 49.115 1.00 60.22 1446 CA GLY 706 62.036 19.100 48.500 1.00 61.75 1447 C GLY 706 63.159 19.239 49.518 1.00 60.44 1448 O GLY 706 64.168 18.519 49.450 1.00 61.54 1449 N ASN 707 62.974 20.148 50.477 1.00 61.06 1450 CA ASN 707 63.989 20.387 51.491 1.00 60.61 1451 CB ASN 707 63.561 21.505 52.443 1.00 63.06 1452 CG ASN 707 64.731 22.048 53.258 1.00 60.50 1453 OD1 ASN 707 64.663 23.152 53.803 1.00 61.18 1454 ND2 ASN 707 65.815 21.269 53.342 1.00 61.75 1455 C ASN 707 64.355 19.143 52.281 1.00 61.56 1456 O ASN 707 63.685 18.767 53.250 1.00 63.56 1457 N SER 708 65.446 18.525 51.837 1.00 62.02 1458 CA SER 708 66.024 17.326 52.427 1.00 60.22 1459 CB SER 708 67.379 17.070 51.737 1.00 58.91 1460 OG SER 708 68.112 15.998 52.305 1.00 62.15 1461 C SER 708 66.200 17.500 53.945 1.00 63.60 1462 O SER 708 66.754 16.635 54.624 1.00 60.95 1463 N SER 709 65.713 18.619 54.474 1.00 61.83 1464 CA SER 709 65.826 18.922 55.894 1.00 61.35 1465 CB SER 709 66.279 20.373 56.065 1.00 65.65 1466 OG SER 709 67.479 20.615 55.332 1.00 62.14 1467 C SER 709 64.516 18.684 56.641 1.00 59.54 1468 O SER 709 64.497 18.583 57.874 1.00 61.29 1469 N GLN 710 63.416 18.586 55.900 1.00 62.57 1470 CA GLN 710 62.131 18.347 56.533 1.00 61.59 1471 CB GLN 710 61.087 19.333 56.007 1.00 58.05 1472 CG GLN 710 61.469 20.792 56.249 1.00 62.98 1473 CD GLN 710 60.344 21.776 55.943 1.00 59.84 1474 OE1 GLN 710 59.363 21.882 56.696 1.00 60.97 1475 NE2 GLN 710 60.481 22.502 54.831 1.00 65.14 1476 C GLN 710 61.683 16.917 56.297 1.00 58.31 1477 O GLN 710 60.512 16.586 56.466 1.00 60.42 1478 N ASN 711 62.625 16.063 55.916 1.00 61.21 1479 CA ASN 711 62.309 14.666 55.673 1.00 63.02 1480 CB ASN 711 63.407 14.033 54.819 1.00 60.49 1481 CG ASN 711 63.508 14.675 53.449 1.00 65.80 1482 OD1 ASN 711 62.565 15.303 52.977 1.00 63.88 1483 ND2 ASN 711 64.646 14.507 52.801 1.00 60.91 1484 C ASN 711 62.090 13.879 56.974 1.00 63.26 1485 O ASN 711 61.055 13.238 57.155 1.00 58.14 1486 N TRP 712 63.054 13.930 57.883 1.00 61.93 1487 CA TRP 712 62.915 13.234 59.148 1.00 59.49 1488 CB TRP 712 64.259 13.185 59.833 1.00 62.44 1489 CG TRP 712 65.169 12.333 59.088 1.00 62.60 1490 CD2 TRP 712 65.485 10.980 59.388 1.00 61.74 1491 CE2 TRP 712 66.331 10.516 58.366 1.00 62.04 1492 CE3 TRP 712 65.130 10.108 60.426 1.00 60.92 1493 CD1 TRP 712 65.815 12.637 57.934 1.00 57.10 1494 NE1 TRP 712 66.517 11.552 57.490 1.00 63.63 1495 CZ2 TRP 712 66.832 9.215 58.345 1.00 63.94 1496 CZ3 TRP 712 65.625 8.817 60.407 1.00 65.64 1497 CH2 TRP 712 66.470 8.381 59.370 1.00 62.08 1498 C TRP 712 61.903 13.954 60.021 1.00 59.14 1499 O TRP 712 61.372 13.410 60.996 1.00 59.32 1500 N GLN 713 61.637 15.191 59.640 1.00 60.06 1501 CA GLN 713 60.705 16.043 60.345 1.00 63.93 1502 CB GLN 713 60.853 17.455 59.793 1.00 59.11 1503 CG GLN 713 60.727 18.564 60.802 1.00 61.74 1504 CD GLN 713 59.352 19.135 60.838 1.00 60.27 1505 OE1 GLN 713 58.660 19.154 59.824 1.00 58.27 1506 NE2 GLN 713 58.942 19.628 61.998 1.00 65.68 1507 C GLN 713 59.296 15.522 60.107 1.00 57.87 1508 O GLN 713 58.472 15.465 61.018 1.00 63.21 1509 N ARG 714 59.051 15.125 58.864 1.00 62.15 1510 CA ARG 714 57.758 14.626 58.424 1.00 57.88 1511 CB ARG 714 57.668 14.782 56.907 1.00 65.30 1512 CG ARG 714 56.272 14.971 56.382 1.00 62.96 1513 CD ARG 714 56.301 15.439 54.940 1.00 62.68 1514 NE ARG 714 55.029 15.200 54.267 1.00 62.08 1515 CZ ARG 714 53.899 15.828 54.561 1.00 62.26 1516 NH1 ARG 714 53.877 16.741 55.515 1.00 59.12 1517 NH2 ARG 714 52.788 15.535 53.906 1.00 57.33 1518 C ARG 714 57.573 13.171 58.831 1.00 60.95 1519 O ARG 714 56.531 12.787 59.368 1.00 60.00 1520 N PHE 715 58.594 12.363 58.571 1.00 59.93 1521 CA PHE 715 58.551 10.960 58.940 1.00 61.38 1522 CB PHE 715 59.934 10.328 58.799 1.00 60.45 1523 CG PHE 715 59.921 8.834 58.843 1.00 63.37 1524 CD1 PHE 715 59.016 8.119 58.063 1.00 61.57 1525 CD2 PHE 715 60.824 8.136 59.636 1.00 59.17 1526 CE1 PHE 715 59.005 6.732 58.067 1.00 60.07 1527 CE2 PHE 715 60.824 6.740 59.648 1.00 58.03 1528 CZ PHE 715 59.904 6.038 58.856 1.00 61.29 1529 C PHE 715 58.118 10.923 60.394 1.00 61.16 1530 O PHE 715 57.409 10.017 60.821 1.00 61.52 1531 N TYR 716 58.541 11.925 61.153 1.00 62.10 1532 CA TYR 716 58.178 11.989 62.550 1.00 61.74 1533 CB TYR 716 58.962 13.092 63.256 1.00 60.58 1534 CG TYR 716 58.729 13.117 64.748 1.00 60.86 1535 CD1 TYR 716 59.376 12.213 65.586 1.00 58.32 1536 CE1 TYR 716 59.159 12.226 66.952 1.00 59.67 1537 CD2 TYR 716 57.852 14.032 65.318 1.00 60.64 1538 CE2 TYR 716 57.625 14.052 66.679 1.00 63.17 1539 CZ TYR 716 58.283 13.152 67.493 1.00 58.37 1540 OH TYR 716 58.090 13.194 68.856 1.00 59.28 1541 C TYR 716 56.688 12.280 62.662 1.00 61.28 1542 O TYR 716 55.952 11.578 63.356 1.00 61.70 1543 N GLN 717 56.249 13.318 61.967 1.00 62.49 1544 CA GLN 717 54.858 13.716 62.009 1.00 63.77 1545 CB GLN 717 54.694 15.061 61.304 1.00 63.18 1546 CG GLN 717 55.613 16.126 61.888 1.00 62.93 1547 CD GLN 717 55.418 17.512 61.288 1.00 62.21 1548 OE1 GLN 717 55.545 17.709 60.073 1.00 59.68 1549 NE2 GLN 717 55.125 18.487 62.147 1.00 58.70 1550 C GLN 717 53.910 12.674 61.426 1.00 61.09 1551 O GLN 717 52.907 12.338 62.064 1.00 61.62 1552 N LEU 718 54.228 12.154 60.237 1.00 62.25 1553 CA LEU 718 53.384 11.144 59.589 1.00 60.93 1554 CB LEU 718 53.880 10.833 58.166 1.00 61.18 1555 CG LEU 718 53.823 11.915 57.078 1.00 60.69 1556 CD1 LEU 718 54.322 11.353 55.764 1.00 59.94 1557 CD2 LEU 718 52.411 12.419 56.916 1.00 64.72 1558 C LEU 718 53.308 9.847 60.391 1.00 61.41 1559 O LEU 718 52.241 9.270 60.530 1.00 62.27 1560 N THR 719 54.441 9.387 60.911 1.00 62.60 1561 CA THR 719 54.469 8.162 61.706 1.00 61.77 1562 CB THR 719 55.902 7.717 62.001 1.00 63.38 1563 OG1 THR 719 56.590 8.749 62.715 1.00 59.25 1564 CG2 THR 719 56.626 7.420 60.716 1.00 64.41 1565 C THR 719 53.744 8.362 63.034 1.00 64.18 1566 O THR 719 53.365 7.398 63.702 1.00 59.43 1567 N LYS 720 53.562 9.619 63.421 1.00 60.48 1568 CA LYS 720 52.864 9.913 64.652 1.00 60.21 1569 CB LYS 720 53.414 11.194 65.281 1.00 63.61 1570 CG LYS 720 52.661 11.630 66.532 1.00 60.31 1571 CD LYS 720 52.340 10.450 67.448 1.00 57.45 1572 CE LYS 720 51.254 10.801 68.472 1.00 57.33 1573 NZ LYS 720 50.621 9.562 69.037 1.00 61.89 1574 C LYS 720 51.364 10.023 64.345 1.00 60.76 1575 O LYS 720 50.523 10.016 65.246 1.00 60.43 1576 N LEU 721 51.030 10.110 63.061 1.00 65.16 1577 CA LEU 721 49.634 10.162 62.659 1.00 59.83 1578 CB LEU 721 49.505 10.724 61.235 1.00 59.18 1579 CG LEU 721 48.264 11.548 60.867 1.00 63.18 1580 CD1 LEU 721 48.219 11.751 59.366 1.00 62.00 1581 CD2 LEU 721 47.005 10.851 61.327 1.00 62.08 1582 C LEU 721 49.163 8.696 62.703 1.00 61.87 1583 O LEU 721 48.041 8.405 63.117 1.00 62.35 1584 N LEU 722 50.052 7.788 62.282 1.00 62.99 1585 CA LEU 722 49.813 6.339 62.250 1.00 58.34 1586 CB LEU 722 50.988 5.635 61.570 1.00 59.92 1587 CG LEU 722 51.194 5.933 60.084 1.00 60.23 1588 CD1 LEU 722 52.500 5.333 59.636 1.00 58.33 1589 CD2 LEU 722 50.050 5.373 59.264 1.00 59.18 1590 C LEU 722 49.624 5.754 63.651 1.00 62.26 1591 O LEU 722 48.827 4.835 63.860 1.00 60.80 1592 N ASP 723 50.389 6.282 64.597 1.00 60.29 1593 CA ASP 723 50.321 5.870 65.989 1.00 61.98 1594 CB ASP 723 51.409 6.583 66.780 1.00 62.74 1595 CG ASP 723 52.652 5.759 66.935 1.00 62.09 1596 OD1 ASP 723 52.840 4.814 66.146 1.00 62.64 1597 OD2 ASP 723 53.445 6.066 67.848 1.00 60.13 1598 C ASP 723 48.970 6.275 66.554 1.00 61.71 1599 O ASP 723 48.281 5.496 67.202 1.00 61.64 1600 N SER 724 48.612 7.524 66.305 1.00 62.20 1601 CA SER 724 47.362 8.090 66.784 1.00 61.12 1602 CB SER 724 47.329 9.579 66.449 1.00 63.08 1603 OG SER 724 47.513 9.767 65.057 1.00 61.03 1604 C SER 724 46.098 7.419 66.246 1.00 59.27 1605 O SER 724 45.015 7.664 66.772 1.00 61.79 1606 N MET 725 46.229 6.594 65.203 1.00 60.63 1607 CA MET 725 45.077 5.893 64.615 1.00 60.05 1608 CB MET 725 45.425 5.228 63.272 1.00 60.16 1609 CG MET 725 45.452 6.151 62.055 1.00 66.62 1610 SD MET 725 43.992 7.180 61.838 1.00 58.95 1611 CE MET 725 42.904 6.134 61.000 1.00 61.36 1612 C MET 725 44.573 4.833 65.576 1.00 64.25 1613 O MET 725 43.382 4.543 65.627 1.00 59.89 1614 N HIS 726 45.492 4.251 66.334 1.00 62.22 1615 CA HIS 726 45.122 3.249 67.313 1.00 60.86 1616 CB HIS 726 46.356 2.746 68.064 1.00 58.90 1617 CG HIS 726 47.183 1.772 67.286 1.00 59.73 1618 CD2 HIS 726 48.518 1.706 67.070 1.00 60.15 1619 ND1 HIS 726 46.635 0.682 66.646 1.00 61.70 1620 CE1 HIS 726 47.598 −0.014 66.069 1.00 61.05 1621 NE2 HIS 726 48.750 0.586 66.311 1.00 60.76 1622 C HIS 726 44.141 3.880 68.291 1.00 61.09 1623 O HIS 726 43.146 3.268 68.650 1.00 60.43 1624 N GLU 727 44.425 5.109 68.714 1.00 61.91 1625 CA GLU 727 43.548 5.825 69.642 1.00 58.28 1626 CB GLU 727 44.218 7.109 70.159 1.00 63.92 1627 CG GLU 727 43.254 8.102 70.846 1.00 59.43 1628 CD GLU 727 43.073 9.413 70.053 1.00 61.79 1629 OE1 GLU 727 44.079 10.150 69.874 1.00 60.96 1630 OE2 GLU 727 41.931 9.707 69.607 1.00 63.98 1631 C GLU 727 42.220 6.187 68.993 1.00 60.97 1632 O GLU 727 41.163 6.009 69.596 1.00 58.72 1633 N VAL 728 42.263 6.699 67.769 1.00 60.50 1634 CA VAL 728 41.022 7.073 67.105 1.00 60.74 1635 CB VAL 728 41.289 7.922 65.828 1.00 58.90 1636 CG1 VAL 728 42.719 7.804 65.415 1.00 58.73 1637 CG2 VAL 728 40.382 7.494 64.703 1.00 65.58 1638 C VAL 728 40.192 5.842 66.773 1.00 59.91 1639 O VAL 728 38.971 5.844 66.931 1.00 61.17 1640 N VAL 729 40.872 4.792 66.326 1.00 61.77 1641 CA VAL 729 40.243 3.522 65.974 1.00 62.39 1642 CB VAL 729 41.277 2.578 65.332 1.00 60.27 1643 CG1 VAL 729 40.946 1.131 65.606 1.00 61.53 1644 CG2 VAL 729 41.298 2.815 63.866 1.00 60.01 1645 C VAL 729 39.586 2.830 67.173 1.00 61.69 1646 O VAL 729 38.718 1.971 67.009 1.00 59.65 1647 N GLU 730 39.999 3.199 68.377 1.00 59.90 1648 CA GLU 730 39.411 2.601 69.558 1.00 60.27 1649 CB GLU 730 40.308 2.812 70.755 1.00 59.45 1650 CG GLU 730 39.878 2.014 71.942 1.00 66.48 1651 CD GLU 730 40.681 2.348 73.167 1.00 62.84 1652 OE1 GLU 730 41.912 2.547 73.039 1.00 61.03 1653 OE2 GLU 730 40.081 2.400 74.263 1.00 60.34 1654 C GLU 730 38.085 3.291 69.804 1.00 62.24 1655 O GLU 730 37.031 2.660 69.869 1.00 60.10 1656 N ASN 731 38.154 4.606 69.941 1.00 61.01 1657 CA ASN 731 36.967 5.409 70.157 1.00 60.41 1658 CB ASN 731 37.356 6.880 70.212 1.00 62.98 1659 CG ASN 731 37.593 7.333 71.613 1.00 59.54 1660 OD1 ASN 731 36.657 7.385 72.410 1.00 58.59 1661 ND2 ASN 731 38.841 7.638 71.945 1.00 58.18 1662 C ASN 731 35.917 5.165 69.081 1.00 61.30 1663 O ASN 731 34.720 5.345 69.317 1.00 60.95 1664 N LEU 732 36.364 4.750 67.902 1.00 60.39 1665 CA LEU 732 35.442 4.475 66.820 1.00 61.55 1666 CB LEU 732 36.141 4.550 65.471 1.00 59.24 1667 CG LEU 732 36.184 5.931 64.813 1.00 64.00 1668 CD1 LEU 732 36.712 5.787 63.374 1.00 62.90 1669 CD2 LEU 732 34.771 6.561 64.818 1.00 60.26 1670 C LEU 732 34.841 3.108 66.997 1.00 60.27 1671 O LEU 732 33.648 2.922 66.774 1.00 61.79 1672 N LEU 733 35.673 2.148 67.399 1.00 58.72 1673 CA LEU 733 35.214 0.770 67.612 1.00 60.63 1674 CB LEU 733 36.376 −0.153 67.969 1.00 60.85 1675 CG LEU 733 37.087 −0.798 66.782 1.00 56.83 1676 CD1 LEU 733 38.344 −1.474 67.266 1.00 63.66 1677 CD2 LEU 733 36.159 −1.786 66.083 1.00 56.09 1678 C LEU 733 34.158 0.663 68.696 1.00 60.11 1679 O LEU 733 33.092 0.098 68.458 1.00 60.20 1680 N ASN 734 34.456 1.192 69.883 1.00 64.88 1681 CA ASN 734 33.503 1.148 70.988 1.00 60.87 1682 CB ASN 734 33.874 2.130 72.099 1.00 64.42 1683 CG ASN 734 35.076 1.683 72.896 1.00 60.85 1684 OD1 ASN 734 35.499 0.526 72.817 1.00 60.20 1685 ND2 ASN 734 35.627 2.597 73.686 1.00 62.04 1686 C ASN 734 32.157 1.544 70.455 1.00 59.98 1687 O ASN 734 31.209 0.755 70.478 1.00 59.10 1688 N TYR 735 32.085 2.778 69.969 1.00 61.85 1689 CA TYR 735 30.844 3.294 69.421 1.00 63.27 1690 CB TYR 735 31.075 4.640 68.743 1.00 60.68 1691 CG TYR 735 29.867 5.515 68.853 1.00 62.56 1692 CD1 TYR 735 28.777 5.328 67.975 1.00 60.84 1693 CE1 TYR 735 27.586 6.030 68.168 1.00 60.10 1694 CD2 TYR 735 29.722 6.421 69.889 1.00 62.93 1695 CE2 TYR 735 28.543 7.127 70.084 1.00 62.59 1696 CZ TYR 735 27.483 6.916 69.221 1.00 60.99 1697 OH TYR 735 26.305 7.561 69.418 1.00 56.15 1698 C TYR 735 30.261 2.306 68.418 1.00 57.10 1699 O TYR 735 29.052 2.158 68.321 1.00 60.19 1700 N CYS 736 31.126 1.621 67.682 1.00 62.53 1701 CA CYS 736 30.673 0.644 66.707 1.00 60.21 1702 CB CYS 736 31.842 0.208 65.815 1.00 62.29 1703 SG CYS 736 31.461 −1.142 64.660 1.00 62.77 1704 C CYS 736 30.063 −0.572 67.399 1.00 62.99 1705 O CYS 736 28.857 −0.795 67.290 1.00 61.76 1706 N PHE 737 30.892 −1.346 68.111 1.00 60.76 1707 CA PHE 737 30.435 −2.546 68.835 1.00 61.61 1708 CB PHE 737 31.454 −3.013 69.889 1.00 65.67 1709 CG PHE 737 32.718 −3.575 69.321 1.00 61.17 1710 CD1 PHE 737 32.732 −4.173 68.069 1.00 62.43 1711 CD2 PHE 737 33.904 −3.515 70.049 1.00 62.09 1712 CE1 PHE 737 33.908 −4.704 67.544 1.00 60.80 1713 CE2 PHE 737 35.083 −4.042 69.536 1.00 61.51 1714 CZ PHE 737 35.086 −4.638 68.279 1.00 59.32 1715 C PHE 737 29.151 −2.266 69.581 1.00 60.98 1716 O PHE 737 28.103 −2.865 69.312 1.00 61.98 1717 N GLN 738 29.274 −1.356 70.542 1.00 64.21 1718 CA GLN 738 28.183 −0.934 71.399 1.00 63.22 1719 CB GLN 738 28.613 0.301 72.173 1.00 64.29 1720 CG GLN 738 27.542 0.896 73.021 1.00 59.02 1721 CD GLN 738 27.555 2.392 72.920 1.00 61.20 1722 OE1 GLN 738 27.116 2.962 71.916 1.00 60.80 1723 NE2 GLN 738 28.082 3.048 73.948 1.00 57.12 1724 C GLN 738 26.917 −0.640 70.606 1.00 61.18 1725 O GLN 738 25.827 −1.017 71.009 1.00 61.34 1726 N THR 739 27.056 0.037 69.478 1.00 61.45 1727 CA THR 739 25.893 0.326 68.678 1.00 60.85 1728 CB THR 739 26.208 1.297 67.542 1.00 55.90 1729 OG1 THR 739 26.212 2.649 68.047 1.00 60.51 1730 CG2 THR 739 25.193 1.200 66.444 1.00 62.24 1731 C THR 739 25.330 −0.969 68.085 1.00 62.53 1732 O THR 739 24.122 −1.107 67.898 1.00 60.85 1733 N PHE 740 26.221 −1.906 67.784 1.00 61.25 1734 CA PHE 740 25.859 −3.197 67.215 1.00 59.86 1735 CB PHE 740 27.110 −3.854 66.641 1.00 60.28 1736 CG PHE 740 26.937 −5.301 66.311 1.00 63.82 1737 CD1 PHE 740 26.434 −5.690 65.079 1.00 62.86 1738 CD2 PHE 740 27.297 −6.278 67.236 1.00 61.71 1739 CE1 PHE 740 26.295 −7.042 64.763 1.00 60.86 1740 CE2 PHE 740 27.165 −7.623 66.938 1.00 60.83 1741 CZ PHE 740 26.663 −8.013 65.696 1.00 60.77 1742 C PHE 740 25.200 −4.140 68.238 1.00 60.76 1743 O PHE 740 24.420 −5.028 67.866 1.00 60.72 1744 N LEU 741 25.538 −3.965 69.515 1.00 62.82 1745 CA LEU 741 24.976 −4.793 70.584 1.00 61.57 1746 CB LEU 741 25.991 −5.012 71.708 1.00 59.14 1747 CG LEU 741 27.187 −5.904 71.404 1.00 62.48 1748 CD1 LEU 741 28.083 −5.956 72.627 1.00 58.13 1749 CD2 LEU 741 26.708 −7.294 71.021 1.00 60.31 1750 C LEU 741 23.770 −4.087 71.165 1.00 60.19 1751 O LEU 741 23.577 −4.055 72.389 1.00 59.64 1752 N ASP 742 22.960 −3.508 70.290 1.00 61.92 1753 CA ASP 742 21.789 −2.797 70.762 1.00 60.22 1754 CB ASP 742 22.185 −1.372 71.179 1.00 61.70 1755 CG ASP 742 21.021 −0.598 71.793 1.00 60.82 1756 OD1 ASP 742 21.258 0.438 72.473 1.00 60.77 1757 OD2 ASP 742 19.863 −1.028 71.587 1.00 61.09 1758 C ASP 742 20.689 −2.769 69.710 1.00 61.90 1759 O ASP 742 20.530 −1.782 68.995 1.00 61.23 1760 N LYS 743 19.934 −3.864 69.623 1.00 63.29 1761 CA LYS 743 18.833 −3.975 68.664 1.00 62.18 1762 CB LYS 743 18.045 −5.273 68.888 1.00 63.55 1763 CG LYS 743 18.054 −6.243 67.705 1.00 62.77 1764 CD LYS 743 17.301 −5.691 66.489 1.00 59.38 1765 CE LYS 743 17.291 −6.724 65.349 1.00 62.80 1766 NZ LYS 743 16.446 −6.335 64.166 1.00 57.45 1767 C LYS 743 17.899 −2.786 68.822 1.00 62.93 1768 O LYS 743 17.407 −2.248 67.833 1.00 58.22 1769 N THR 744 17.669 −2.383 70.069 1.00 61.23 1770 CA THR 744 16.808 −1.247 70.400 1.00 61.48 1771 CB THR 744 17.148 −0.715 71.802 1.00 63.18 1772 OG1 THR 744 17.199 −1.817 72.719 1.00 59.84 1773 CG2 THR 744 16.112 0.308 72.265 1.00 60.98 1774 C THR 744 16.913 −0.077 69.411 1.00 59.67 1775 O THR 744 15.913 0.580 69.118 1.00 64.20 1776 N MET 745 18.117 0.184 68.903 1.00 61.36 1777 CA MET 745 18.322 1.282 67.961 1.00 62.05 1778 CB MET 745 19.703 1.909 68.158 1.00 63.01 1779 CG MET 745 20.029 2.189 69.614 1.00 61.21 1780 SD MET 745 21.418 3.324 69.877 1.00 62.14 1781 CE MET 745 20.934 4.087 71.538 1.00 61.78 1782 C MET 745 18.175 0.824 66.517 1.00 59.56 1783 O MET 745 18.382 1.605 65.585 1.00 62.58 1784 N SER 746 17.817 −0.442 66.334 1.00 59.78 1785 CA SER 746 17.624 −1.000 64.996 1.00 58.09 1786 CB SER 746 16.169 −0.786 64.541 1.00 58.34 1787 OG SER 746 15.252 −1.368 65.455 1.00 63.83 1788 C SER 746 18.592 −0.429 63.940 1.00 59.09 1789 O SER 746 18.176 0.027 62.867 1.00 61.57 1790 N ILE 747 19.882 −0.432 64.269 1.00 62.10 1791 CA ILE 747 20.905 0.022 63.342 1.00 61.22 1792 CB ILE 747 22.021 0.814 64.054 1.00 63.05 1793 CG2 ILE 747 23.241 0.930 63.145 1.00 64.60 1794 CG1 ILE 747 21.499 2.205 64.426 1.00 61.38 1795 CD1 ILE 747 22.576 3.198 64.804 1.00 63.35 1796 C ILE 747 21.465 −1.260 62.749 1.00 62.54 1797 O ILE 747 22.169 −2.011 63.419 1.00 60.09 1798 N GLU 748 21.125 −1.507 61.491 1.00 60.25 1799 CA GLU 748 21.541 −2.711 60.787 1.00 60.97 1800 CB GLU 748 20.497 −3.038 59.709 1.00 63.45 1801 CG GLU 748 20.877 −4.168 58.756 1.00 60.81 1802 CD GLU 748 19.678 −4.723 57.973 1.00 59.13 1803 OE1 GLU 748 19.013 −3.932 57.262 1.00 62.39 1804 OE2 GLU 748 19.406 −5.950 58.072 1.00 61.13 1805 C GLU 748 22.940 −2.658 60.175 1.00 61.28 1806 O GLU 748 23.391 −1.616 59.690 1.00 62.62 1807 N PHE 749 23.622 −3.800 60.231 1.00 62.73 1808 CA PHE 749 24.963 −3.959 59.667 1.00 59.35 1809 CB PHE 749 25.974 −4.421 60.733 1.00 59.45 1810 CG PHE 749 26.299 −3.389 61.759 1.00 64.74 1811 CD1 PHE 749 25.399 −3.085 62.770 1.00 59.18 1812 CD2 PHE 749 27.514 −2.721 61.721 1.00 57.96 1813 CE1 PHE 749 25.708 −2.119 63.742 1.00 61.52 1814 CE2 PHE 749 27.839 −1.753 62.685 1.00 65.31 1815 CZ PHE 749 26.934 −1.451 63.697 1.00 59.87 1816 C PHE 749 24.872 −5.048 58.599 1.00 60.75 1817 O PHE 749 24.047 −5.952 58.705 1.00 62.03 1818 N PRO 750 25.705 −4.970 57.550 1.00 61.23 1819 CD PRO 750 26.645 −3.910 57.166 1.00 60.04 1820 CA PRO 750 25.652 −6.003 56.516 1.00 61.34 1821 CB PRO 750 26.584 −5.468 55.434 1.00 64.04 1822 CG PRO 750 26.608 −4.015 55.668 1.00 60.17 1823 C PRO 750 26.240 −7.235 57.172 1.00 60.83 1824 O PRO 750 26.788 −7.143 58.271 1.00 59.53 1825 N GLU 751 26.139 −8.386 56.523 1.00 60.43 1826 CA GLU 751 26.719 −9.572 57.122 1.00 61.33 1827 CB GLU 751 26.350 −10.834 56.311 1.00 62.90 1828 CG GLU 751 25.560 −10.608 55.002 1.00 60.51 1829 CD GLU 751 26.436 −10.142 53.837 1.00 57.86 1830 OE1 GLU 751 27.420 −10.844 53.519 1.00 60.97 1831 OE2 GLU 751 26.138 −9.084 53.240 1.00 59.16 1832 C GLU 751 28.255 −9.389 57.219 1.00 58.48 1833 O GLU 751 28.850 −9.561 58.292 1.00 59.47 1834 N MET 752 28.891 −9.004 56.115 1.00 64.26 1835 CA MET 752 30.336 −8.808 56.109 1.00 61.15 1836 CB MET 752 30.777 −8.060 54.857 1.00 63.84 1837 CG MET 752 32.255 −7.666 54.898 1.00 64.44 1838 SD MET 752 33.383 −9.076 55.043 1.00 67.15 1839 CE MET 752 33.649 −9.386 53.307 1.00 59.96 1840 C MET 752 30.884 −8.072 57.323 1.00 62.38 1841 O MET 752 31.963 −8.394 57.811 1.00 60.81 1842 N LEU 753 30.163 −7.067 57.796 1.00 59.19 1843 CA LEU 753 30.627 −6.323 58.957 1.00 62.39 1844 CB LEU 753 30.187 −4.862 58.881 1.00 61.65 1845 CG LEU 753 31.214 −3.835 58.397 1.00 61.49 1846 CD1 LEU 753 31.713 −4.171 57.010 1.00 61.11 1847 CD2 LEU 753 30.567 −2.471 58.411 1.00 63.29 1848 C LEU 753 30.114 −6.946 60.241 1.00 58.84 1849 O LEU 753 30.779 −6.885 61.273 1.00 61.39 1850 N ALA 754 28.927 −7.541 60.177 1.00 62.56 1851 CA ALA 754 28.337 −8.194 61.343 1.00 61.99 1852 CB ALA 754 26.963 −8.775 60.983 1.00 59.37 1853 C ALA 754 29.287 −9.313 61.747 1.00 66.01 1854 O ALA 754 29.619 −9.482 62.922 1.00 63.54 1855 N GLU 755 29.724 −10.044 60.722 1.00 63.92 1856 CA GLU 755 30.632 −11.194 60.795 1.00 59.42 1857 CB GLU 755 30.674 −11.851 59.407 1.00 60.24 1858 CG GLU 755 31.733 −12.933 59.190 1.00 62.29 1859 CD GLU 755 31.348 −14.260 59.811 1.00 59.60 1860 OE1 GLU 755 30.318 −14.834 59.388 1.00 60.67 1861 OE2 GLU 755 32.075 −14.728 60.719 1.00 62.46 1862 C GLU 755 32.068 −10.912 61.252 1.00 60.75 1863 O GLU 755 32.906 −11.809 61.240 1.00 61.42 1864 N ILE 756 32.363 −9.677 61.636 1.00 60.43 1865 CA ILE 756 33.709 −9.328 62.074 1.00 65.41 1866 CB ILE 756 34.369 −8.336 61.114 1.00 58.24 1867 CG2 ILE 756 35.741 −7.964 61.623 1.00 57.70 1868 CG1 ILE 756 34.478 −8.957 59.729 1.00 59.57 1869 CD1 ILE 756 35.178 −8.090 58.743 1.00 61.24 1870 C ILE 756 33.625 −8.693 63.439 1.00 63.18 1871 O ILE 756 34.373 −9.043 64.351 1.00 58.77 1872 N ILE 757 32.705 −7.740 63.548 1.00 59.89 1873 CA ILE 757 32.434 −7.024 64.785 1.00 61.90 1874 CB ILE 757 31.115 −6.254 64.668 1.00 64.77 1875 CG2 ILE 757 30.778 −5.602 65.991 1.00 62.61 1876 CG1 ILE 757 31.224 −5.237 63.529 1.00 62.60 1877 CD1 ILE 757 29.902 −4.649 63.097 1.00 59.02 1878 C ILE 757 32.298 −8.069 65.879 1.00 60.76 1879 O ILE 757 32.990 −8.016 66.890 1.00 60.98 1880 N THR 758 31.396 −9.022 65.660 1.00 59.72 1881 CA THR 758 31.184 −10.104 66.608 1.00 61.21 1882 CB THR 758 30.224 −11.141 66.017 1.00 58.63 1883 OG1 THR 758 30.260 −11.028 64.592 1.00 60.88 1884 CG2 THR 758 28.792 −10.925 66.527 1.00 60.75 1885 C THR 758 32.540 −10.770 66.885 1.00 61.53 1886 O THR 758 33.167 −10.549 67.926 1.00 61.44 1887 N ASN 759 32.979 −11.572 65.924 1.00 62.04 1888 CA ASN 759 34.240 −12.305 65.965 1.00 60.58 1889 CB ASN 759 34.426 −13.001 64.623 1.00 60.54 1890 CG ASN 759 33.242 −12.774 63.689 1.00 60.06 1891 OD1 ASN 759 32.581 −11.723 63.736 1.00 59.27 1892 ND2 ASN 759 32.976 −13.747 62.825 1.00 59.97 1893 C ASN 759 35.470 −11.432 66.249 1.00 59.08 1894 O ASN 759 36.564 −11.710 65.734 1.00 63.02 1895 N GLN 760 35.282 −10.388 67.059 1.00 60.43 1896 CA GLN 760 36.336 −9.442 67.438 1.00 61.43 1897 CB GLN 760 36.620 −8.446 66.302 1.00 56.98 1898 CG GLN 760 37.445 −8.966 65.121 1.00 61.31 1899 CD GLN 760 38.839 −9.446 65.514 1.00 63.88 1900 OE1 GLN 760 39.445 −8.949 66.463 1.00 59.43 1901 NE2 GLN 760 39.356 −10.409 64.769 1.00 62.96 1902 C GLN 760 35.850 −8.659 68.651 1.00 59.31 1903 O GLN 760 36.625 −8.353 69.563 1.00 59.88 1904 N ILE 761 34.546 −8.371 68.649 1.00 61.08 1905 CA ILE 761 33.861 −7.606 69.704 1.00 64.40 1906 CB ILE 761 32.318 −7.582 69.469 1.00 60.77 1907 CG2 ILE 761 31.759 −8.983 69.575 1.00 61.46 1908 CG1 ILE 761 31.626 −6.686 70.500 1.00 61.86 1909 CD1 ILE 761 30.115 −6.703 70.390 1.00 62.34 1910 C ILE 761 34.111 −8.077 71.139 1.00 63.06 1911 O ILE 761 33.900 −7.317 72.087 1.00 60.11 1912 N PRO 762 34.543 −9.338 71.319 1.00 58.19 1913 CD PRO 762 34.581 −10.454 70.353 1.00 61.52 1914 CA PRO 762 34.800 −9.840 72.670 1.00 60.05 1915 CB PRO 762 34.718 −11.350 72.482 1.00 60.47 1916 CG PRO 762 35.309 −11.528 71.122 1.00 62.98 1917 C PRO 762 36.160 −9.419 73.230 1.00 59.07 1918 O PRO 762 36.257 −8.697 74.232 1.00 61.15 1919 N LYS 763 37.203 −9.887 72.558 1.00 59.41 1920 CA LYS 763 38.580 −9.637 72.960 1.00 61.27 1921 CB LYS 763 39.424 −10.882 72.594 1.00 61.66 1922 CG LYS 763 40.926 −10.651 72.347 1.00 62.08 1923 CD LYS 763 41.206 −9.910 71.025 1.00 58.99 1924 CE LYS 763 40.834 −10.723 69.776 1.00 60.53 1925 NZ LYS 763 39.378 −11.026 69.623 1.00 62.94 1926 C LYS 763 39.256 −8.359 72.438 1.00 63.01 1927 O LYS 763 40.164 −7.846 73.086 1.00 63.43 1928 N TYR 764 38.820 −7.847 71.289 1.00 64.75 1929 CA TYR 764 39.428 −6.653 70.673 1.00 58.42 1930 CB TYR 764 38.399 −5.865 69.876 1.00 62.63 1931 CG TYR 764 38.901 −5.590 68.486 1.00 65.16 1932 CD1 TYR 764 38.708 −6.516 67.467 1.00 57.96 1933 CE1 TYR 764 39.190 −6.287 66.180 1.00 61.30 1934 CD2 TYR 764 39.600 −4.422 68.192 1.00 61.22 1935 CE2 TYR 764 40.092 −4.183 66.902 1.00 61.36 1936 CZ TYR 764 39.876 −5.118 65.901 1.00 59.50 1937 OH TYR 764 40.304 −4.863 64.612 1.00 62.78 1938 C TYR 764 40.204 −5.654 71.535 1.00 61.96 1939 O TYR 764 41.310 −5.963 72.003 1.00 61.04 1940 N SER 765 39.653 −4.443 71.701 1.00 60.29 1941 CA SER 765 40.324 −3.419 72.519 1.00 61.03 1942 CB SER 765 39.780 −1.999 72.208 1.00 57.40 1943 OG SER 765 38.359 −1.934 72.144 1.00 59.00 1944 C SER 765 40.207 −3.760 74.016 1.00 59.80 1945 O SER 765 39.574 −3.046 74.809 1.00 60.59 1946 N ASN 766 40.833 −4.884 74.371 1.00 59.36 1947 CA ASN 766 40.867 −5.404 75.738 1.00 63.02 1948 CB ASN 766 40.390 −6.867 75.745 1.00 59.32 1949 CG ASN 766 38.959 −7.018 75.239 1.00 61.45 1950 OD1 ASN 766 38.593 −6.456 74.197 1.00 60.60 1951 ND2 ASN 766 38.143 −7.782 75.971 1.00 64.82 1952 C ASN 766 42.301 −5.305 76.311 1.00 62.76 1953 O ASN 766 42.503 −4.889 77.469 1.00 60.59 1954 N GLY 767 43.281 −5.673 75.478 1.00 59.11 1955 CA GLY 767 44.689 −5.653 75.860 1.00 59.91 1956 C GLY 767 45.366 −6.867 75.232 1.00 61.75 1957 O GLY 767 46.588 −6.912 75.041 1.00 61.17 1958 N ASN 768 44.532 −7.846 74.887 1.00 62.80 1959 CA ASN 768 44.942 −9.109 74.276 1.00 62.46 1960 CB ASN 768 43.717 −10.032 74.246 1.00 59.72 1961 CG ASN 768 42.798 −9.832 75.467 1.00 60.42 1962 OD1 ASN 768 41.697 −10.404 75.538 1.00 59.89 1963 ND2 ASN 768 43.248 −9.020 76.427 1.00 63.45 1964 C ASN 768 45.543 −8.940 72.855 1.00 63.10 1965 O ASN 768 46.095 −9.882 72.282 1.00 62.80 1966 N ILE 769 45.418 −7.744 72.284 1.00 58.10 1967 CA ILE 769 45.984 −7.464 70.967 1.00 60.18 1968 CB ILE 769 45.006 −6.713 70.036 1.00 61.64 1969 CG2 ILE 769 45.569 −6.703 68.614 1.00 59.97 1970 CG1 ILE 769 43.623 −7.361 70.051 1.00 65.54 1971 CD1 ILE 769 42.605 −6.626 69.175 1.00 65.14 1972 C ILE 769 47.192 −6.544 71.150 1.00 59.44 1973 O ILE 769 47.217 −5.701 72.058 1.00 61.97 1974 N LYS 770 48.175 −6.692 70.267 1.00 61.57 1975 CA LYS 770 49.391 −5.890 70.314 1.00 60.09 1976 CB LYS 770 50.601 −6.778 70.033 1.00 61.51 1977 CG LYS 770 51.961 −6.172 70.339 1.00 61.08 1978 CD LYS 770 53.041 −7.224 70.047 1.00 59.40 1979 CE LYS 770 54.344 −6.982 70.801 1.00 62.15 1980 NZ LYS 770 55.339 −8.089 70.604 1.00 63.19 1981 C LYS 770 49.333 −4.776 69.277 1.00 63.90 1982 O LYS 770 49.439 −5.031 68.071 1.00 62.08 1983 N LYS 771 49.161 −3.545 69.754 1.00 59.06 1984 CA LYS 771 49.103 −2.376 68.884 1.00 61.08 1985 CB LYS 771 48.386 −1.212 69.589 1.00 63.15 1986 CG LYS 771 49.188 −0.525 70.712 1.00 63.84 1987 CD LYS 771 48.443 0.681 71.308 1.00 63.12 1988 CE LYS 771 49.384 1.588 72.100 1.00 59.83 1989 NZ LYS 771 48.821 2.970 72.186 1.00 60.16 1990 C LYS 771 50.532 −1.976 68.550 1.00 60.42 1991 O LYS 771 51.276 −1.561 69.430 1.00 62.03 1992 N LEU 772 50.928 −2.120 67.290 1.00 60.80 1993 CA LEU 772 52.285 −1.756 66.890 1.00 58.97 1994 CB LEU 772 52.629 −2.368 65.533 1.00 62.77 1995 CG LEU 772 52.781 −3.885 65.492 1.00 63.82 1996 CD1 LEU 772 52.780 −4.346 64.046 1.00 62.61 1997 CD2 LEU 772 54.071 −4.295 66.203 1.00 63.11 1998 C LEU 772 52.405 −0.243 66.812 1.00 61.57 1999 O LEU 772 51.513 0.428 66.289 1.00 60.62 2000 N LEU 773 53.499 0.296 67.341 1.00 59.76 2001 CA LEU 773 53.704 1.734 67.317 1.00 60.00 2002 CB LEU 773 53.602 2.320 68.725 1.00 59.66 2003 CG LEU 773 52.221 2.321 69.380 1.00 62.80 2004 CD1 LEU 773 52.290 2.999 70.729 1.00 61.23 2005 CD2 LEU 773 51.233 3.053 68.490 1.00 65.68 2006 C LEU 773 55.051 2.094 66.727 1.00 62.80 2007 O LEU 773 55.911 1.234 66.517 1.00 61.81 2008 N PHE 774 55.219 3.382 66.456 1.00 60.94 2009 CA PHE 774 56.451 3.917 65.897 1.00 61.49 2010 GB PHE 774 56.128 4.864 64.743 1.00 63.45 2011 CG PHE 774 55.889 4.169 63.451 1.00 61.20 2012 CD1 PHE 774 56.936 3.532 62.802 1.00 63.76 2013 CD2 PHE 774 54.621 4.105 62.902 1.00 61.89 2014 CE1 PHE 774 56.727 2.838 61.627 1.00 56.93 2015 CE2 PHE 774 54.395 3.409 61.720 1.00 59.92 2016 CZ PHE 774 55.451 2.773 61.081 1.00 62.56 2017 C PHE 774 57.175 4.681 66.984 1.00 60.20 2018 O PHE 774 58.400 4.702 67.046 1.00 60.03 2019 N HIS 775 56.384 5.301 67.849 1.00 62.48 2020 CA HIS 775 56.905 6.104 68.934 1.00 64.64 2021 CB HIS 775 56.466 7.558 68.730 1.00 61.69 2022 CG HIS 775 56.898 8.120 67.417 1.00 59.70 2023 CD2 HIS 775 56.188 8.565 66.356 1.00 62.49 2024 ND1 HIS 775 58.223 8.191 67.047 1.00 60.30 2025 CE1 HIS 775 58.313 8.652 65.813 1.00 59.19 2026 NE2 HIS 775 57.092 8.886 65.370 1.00 59.04 2027 C HIS 775 56.428 5.596 70.277 1.00 64.58 2028 O HIS 775 55.390 4.948 70.373 1.00 58.66 2029 N GLN 776 57.203 5.895 71.311 1.00 60.50 2030 CA GLN 776 56.864 5.502 72.669 1.00 61.43 2031 CB GLN 776 58.154 5.293 73.457 1.00 59.86 2032 CG GLN 776 59.281 6.243 73.042 1.00 57.49 2033 CD GLN 776 60.679 5.638 73.241 1.00 60.53 2034 OE1 GLN 776 61.696 6.265 72.919 1.00 61.97 2035 NE2 GLN 776 60.730 4.412 73.772 1.00 60.63 2036 C GLN 776 55.993 6.583 73.335 1.00 60.06 2037 O GLN 776 56.098 7.765 72.919 1.00 61.84 2038 OXT GLN 776 55.219 6.239 74.268 1.00 60.74 2039 CB GLU 741 35.922 −16.424 65.488 1.00 58.89 2040 CG GLU 741 36.766 −17.078 64.386 1.00 67.76 2041 CD GLU 741 38.144 −16.463 64.277 1.00 60.66 2042 OE1 GLU 741 38.838 −16.698 63.252 1.00 59.66 2043 OE2 GLU 741 38.524 −15.741 65.233 1.00 61.27 2044 C GLU 741 33.996 −16.854 64.024 1.00 61.38 2045 O GLU 741 33.681 −15.808 63.464 1.00 63.70 2046 N GLU 741 34.336 −18.280 65.946 1.00 62.41 2047 CA GLU 741 34.460 −16.870 65.464 1.00 59.35 2048 N GLU 742 33.995 −18.034 63.422 1.00 58.35 2049 CA GLU 742 33.594 −18.184 62.036 1.00 63.61 2050 CB GLU 742 32.158 −17.672 61.824 1.00 60.80 2051 CG GLU 742 31.516 −18.155 60.518 1.00 62.06 2052 CD GLU 742 31.783 −19.645 60.238 1.00 63.64 2053 OE1 GLU 742 31.146 −20.190 59.309 1.00 64.92 2054 OE2 GLU 742 32.632 −20.276 60.925 1.00 62.96 2055 C GLU 742 34.541 −17.482 61.064 1.00 61.07 2056 O GLU 742 35.655 −17.950 60.825 1.00 59.51 2057 N ASN 743 34.090 −16.355 60.522 1.00 61.83 2058 CA ASN 743 34.850 −15.586 59.535 1.00 60.95 2059 CB ASN 743 36.300 −15.368 59.987 1.00 61.82 2060 CG ASN 743 36.418 −14.360 61.118 1.00 64.29 2061 OD1 ASN 743 36.646 −14.729 62.277 1.00 58.19 2062 ND2 ASN 743 36.262 −13.077 60.787 1.00 58.54 2063 C ASN 743 34.842 −16.318 58.192 1.00 60.80 2064 O ASN 743 35.780 −16.196 57.410 1.00 62.67 2065 N ALA 744 33.779 −17.075 57.935 1.00 59.69 2066 CA ALA 744 33.640 −17.827 56.696 1.00 61.76 2067 CB ALA 744 32.350 −18.623 56.729 1.00 60.04 2068 C ALA 744 33.675 −16.930 55.453 1.00 62.63 2069 O ALA 744 34.423 −17.199 54.503 1.00 58.54 2070 N LEU 745 32.869 −15.866 55.462 1.00 60.19 2071 CA LEU 745 32.820 −14.936 54.329 1.00 62.12 2072 CB LEU 745 31.855 −13.783 54.617 1.00 60.59 2073 CG LEU 745 30.606 −13.726 53.739 1.00 58.63 2074 CD1 LEU 745 29.895 −12.400 53.937 1.00 64.25 2075 CD2 LEU 745 31.004 −13.902 52.291 1.00 60.41 2076 C LEU 745 34.190 −14.360 53.952 1.00 61.72 2077 O LEU 745 34.521 −14.276 52.776 1.00 59.83 2078 N LEU 746 34.978 −13.961 54.946 1.00 57.79 2079 CA LEU 746 36.311 −13.413 54.691 1.00 60.45 2080 CB LEU 746 36.898 −12.849 55.989 1.00 61.06 2081 CG LEU 746 37.673 −11.534 55.956 1.00 61.13 2082 CD1 LEU 746 38.380 −11.374 57.275 1.00 61.70 2083 CD2 LEU 746 38.664 −11.520 54.823 1.00 61.56 2084 C LEU 746 37.249 −14.511 54.156 1.00 58.73 2085 O LEU 746 37.905 −14.356 53.120 1.00 62.68 2086 N ARG 747 37.307 −15.613 54.895 1.00 61.00 2087 CA ARG 747 38.145 −16.759 54.560 1.00 57.24 2088 CB ARG 747 37.853 −17.906 55.539 1.00 66.74 2089 CG ARG 747 38.332 −19.278 55.102 1.00 61.05 2090 CD ARG 747 38.533 −20.190 56.319 1.00 62.51 2091 NE ARG 747 39.807 −19.938 56.998 1.00 62.06 2092 CZ ARG 747 39.952 −19.867 58.321 1.00 63.78 2093 NH1 ARG 747 38.894 −20.023 59.118 1.00 60.31 2094 NH2 ARG 747 41.156 −19.637 58.848 1.00 60.80 2095 C ARG 747 37.883 −17.186 53.134 1.00 59.12 2096 O ARG 747 38.793 −17.589 52.418 1.00 62.02 2097 N TYR 748 36.623 −17.088 52.731 1.00 61.89 2098 CA TYR 748 36.215 −17.449 51.387 1.00 65.00 2099 CB TYR 748 34.685 −17.413 51.301 1.00 58.95 2100 CG TYR 748 34.136 −17.350 49.897 1.00 62.12 2101 CD1 TYR 748 34.256 −18.429 49.021 1.00 63.79 2102 CE1 TYR 748 33.805 −18.342 47.715 1.00 61.69 2103 CD2 TYR 748 33.544 −16.185 49.430 1.00 61.63 2104 CE2 TYR 748 33.091 −16.084 48.127 1.00 60.08 2105 CZ TYR 748 33.226 −17.163 47.272 1.00 58.42 2106 OH TYR 748 32.806 −17.030 45.966 1.00 59.74 2107 C TYR 748 36.832 −16.447 50.419 1.00 61.75 2108 O TYR 748 37.599 −16.807 49.532 1.00 61.82 2109 N LEU 749 36.501 −15.178 50.628 1.00 60.52 2110 CA LEU 749 36.974 −14.069 49.800 1.00 61.53 2111 CB LEU 749 36.380 −12.757 50.303 1.00 63.00 2112 CG LEU 749 34.873 −12.741 50.535 1.00 57.09 2113 CD1 LEU 749 34.508 −11.427 51.167 1.00 62.85 2114 CD2 LEU 749 34.113 −12.954 49.233 1.00 62.37 2115 C LEU 749 38.482 −13.910 49.733 1.00 64.05 2116 O LEU 749 38.991 −13.275 48.807 1.00 61.97 2117 N LEU 750 39.195 −14.475 50.703 1.00 59.99 2118 CA LEU 750 40.644 −14.363 50.728 1.00 63.11 2119 CB LEU 750 41.147 −14.497 52.167 1.00 62.65 2120 CG LEU 750 41.463 −13.160 52.849 1.00 63.02 2121 CD1 LEU 750 41.695 −13.344 54.327 1.00 58.04 2122 CD2 LEU 750 42.693 −12.559 52.194 1.00 62.24 2123 C LEU 750 41.436 −15.294 49.803 1.00 64.30 2124 O LEU 750 42.666 −15.246 49.796 1.00 58.24 2125 N ASP 751 40.745 −16.129 49.024 1.00 59.30 2126 CA ASP 751 41.396 −17.048 48.068 1.00 62.49 2127 CB ASP 751 41.860 −18.337 48.764 1.00 62.90 2128 CG ASP 751 40.921 −18.784 49.855 1.00 62.09 2129 OD1 ASP 751 40.342 −17.900 50.526 1.00 62.68 2130 OD2 ASP 751 40.779 −20.014 50.051 1.00 60.33 2131 C ASP 751 40.472 −17.371 46.897 1.00 61.25 2132 O ASP 751 39.476 −18.065 47.053 1.00 61.96 2133 N LYS 752 40.824 −16.849 45.725 1.00 62.34 2134 CA LYS 752 40.030 −17.003 44.506 1.00 62.50 2135 CB LYS 752 38.733 −16.160 44.600 1.00 63.17 2136 CG LYS 752 37.872 −16.386 45.858 1.00 60.82 2137 CD LYS 752 36.923 −15.230 46.159 1.00 62.16 2138 CE LYS 752 35.726 −15.186 45.223 1.00 60.30 2139 NZ LYS 752 36.101 −15.095 43.779 1.00 61.47 2140 C LYS 752 40.895 −16.438 43.384 1.00 63.98 2141 O LYS 752 42.043 −16.833 43.212 1.00 60.08 2142 N ASP 753 40.322 −15.496 42.641 1.00 61.50 2143 CA ASP 753 41.004 −14.809 41.552 1.00 60.87 2144 CB ASP 753 41.969 −13.778 42.151 1.00 61.81 2145 CG ASP 753 41.293 −12.886 43.212 1.00 65.36 2146 OD1 ASP 753 40.845 −13.417 44.262 1.00 58.98 2147 OD2 ASP 753 41.204 −11.653 42.996 1.00 62.40 2148 C ASP 753 41.712 −15.723 40.533 1.00 62.25 2149 O ASP 753 41.905 −16.929 40.770 1.00 62.51 2150 N ASP 754 42.076 −15.125 39.394 1.00 59.26 2151 CA ASP 754 42.713 −15.818 38.271 1.00 62.08 2152 CB ASP 754 42.118 −15.302 36.949 1.00 60.51 2153 CG ASP 754 41.121 −14.148 37.150 1.00 60.95 2154 OD1 ASP 754 40.683 −13.555 36.135 1.00 61.57 2155 OD2 ASP 754 40.762 −13.831 38.304 1.00 61.61 2156 C ASP 754 44.236 −15.678 38.234 1.00 60.21 2157 O ASP 754 44.946 −16.712 38.264 1.00 63.29 2158 OXT ASP 754 44.707 −14.526 38.169 1.00 61.39 2159 CB GLN 527 44.425 43.308 57.458 1.00 59.84 2160 CG GLN 527 45.330 43.181 58.697 1.00 63.06 2161 CD GLN 527 46.173 41.895 58.675 1.00 61.64 2162 OE1 GLN 527 46.913 41.596 59.623 1.00 62.44 2163 NE2 GLN 527 46.065 41.137 57.583 1.00 63.46 2164 C GLN 527 43.994 44.763 55.475 1.00 60.61 2165 O GLN 527 44.711 45.517 54.798 1.00 61.62 2166 N GLN 527 42.843 45.238 57.671 1.00 62.80 2167 CA GLN 527 44.095 44.745 57.006 1.00 60.11 2168 N LEU 528 43.105 43.912 54.955 1.00 62.93 2169 CA LEU 528 42.857 43.747 53.516 1.00 58.92 2170 CB LEU 528 43.696 42.579 52.979 1.00 61.24 2171 CG LEU 528 45.210 42.751 53.124 1.00 58.97 2172 CD1 LEU 528 45.858 41.410 53.501 1.00 57.95 2173 CD2 LEU 528 45.778 43.371 51.831 1.00 60.61 2174 C LEU 528 41.369 43.449 53.303 1.00 63.94 2175 O LEU 528 40.531 44.290 53.650 1.00 62.36 2176 N THR 529 41.067 42.256 52.748 1.00 59.95 2177 CA THR 529 39.689 41.769 52.487 1.00 61.84 2178 CB THR 529 39.396 40.430 53.232 1.00 59.05 2179 OG1 THR 529 40.375 39.442 52.866 1.00 63.83 2180 CG2 THR 529 37.997 39.920 52.882 1.00 59.80 2181 C THR 529 38.725 42.842 52.992 1.00 61.32 2182 O THR 529 37.988 42.645 53.973 1.00 61.35 2183 N PRO 530 38.704 43.977 52.271 1.00 64.25 2184 CD PRO 530 38.650 43.494 50.878 1.00 59.35 2185 CA PRO 530 38.021 45.276 52.317 1.00 58.74 2186 CB PRO 530 37.610 45.502 50.860 1.00 60.27 2187 CG PRO 530 37.368 44.132 50.384 1.00 65.84 2188 C PRO 530 36.839 45.387 53.239 1.00 62.92 2189 O PRO 530 36.948 45.328 54.474 1.00 60.28 2190 N THR 531 35.706 45.591 52.590 1.00 63.85 2191 CA THR 531 34.443 45.708 53.246 1.00 62.34 2192 CB THR 531 34.253 47.135 53.851 1.00 63.80 2193 OG1 THR 531 33.854 47.016 55.230 1.00 64.25 2194 CG2 THR 531 33.218 47.940 53.067 1.00 61.34 2195 C THR 531 33.526 45.410 52.081 1.00 61.78 2196 O THR 531 32.505 44.758 52.251 1.00 61.93 2197 N LEU 532 33.917 45.822 50.877 1.00 62.02 2198 CA LEU 532 33.060 45.545 49.722 1.00 60.94 2199 CB LEU 532 33.410 46.445 48.528 1.00 57.32 2200 CG LEU 532 32.463 46.285 47.329 1.00 64.49 2201 CD1 LEU 532 31.027 46.313 47.771 1.00 61.90 2202 CD2 LEU 532 32.702 47.377 46.344 1.00 62.84 2203 C LEU 532 33.077 44.077 49.283 1.00 61.37 2204 O LEU 532 32.016 43.461 49.149 1.00 62.65 2205 N VAL 533 34.266 43.518 49.052 1.00 61.22 2206 CA VAL 533 34.366 42.119 48.635 1.00 60.75 2207 CB VAL 533 35.781 41.753 48.114 1.00 59.58 2208 CG1 VAL 533 36.697 41.400 49.264 1.00 60.31 2209 CG2 VAL 533 35.695 40.576 47.185 1.00 59.77 2210 C VAL 533 34.062 41.240 49.840 1.00 63.61 2211 O VAL 533 33.861 40.038 49.709 1.00 62.93 2212 N SER 534 34.053 41.859 51.013 1.00 61.64 2213 CA SER 534 33.774 41.170 52.260 1.00 60.61 2214 CB SER 534 34.143 42.089 53.425 1.00 62.32 2215 OG SER 534 34.391 41.364 54.612 1.00 60.70 2216 C SER 534 32.276 40.880 52.270 1.00 62.67 2217 O SER 534 31.799 39.906 52.854 1.00 59.90 2218 N LEU 535 31.544 41.747 51.593 1.00 60.18 2219 CA LEU 535 30.102 41.644 51.508 1.00 60.75 2220 CB LEU 535 29.527 42.975 51.048 1.00 61.59 2221 CG LEU 535 28.027 43.101 51.245 1.00 61.16 2222 CD1 LEU 535 27.773 43.835 52.537 1.00 63.92 2223 CD2 LEU 535 27.416 43.850 50.089 1.00 61.72 2224 C LEU 535 29.688 40.547 50.543 1.00 60.18 2225 O LEU 535 28.852 39.714 50.868 1.00 58.39 2226 N LEU 536 30.269 40.552 49.349 1.00 60.57 2227 CA LEU 536 29.950 39.536 48.355 1.00 63.14 2228 CB LEU 536 30.813 39.719 47.115 1.00 61.69 2229 CG LEU 536 30.671 40.980 46.284 1.00 63.99 2230 CD1 LEU 536 31.622 40.864 45.118 1.00 60.60 2231 CD2 LEU 536 29.247 41.145 45.801 1.00 62.81 2232 C LEU 536 30.204 38.140 48.908 1.00 61.72 2233 O LEU 536 29.703 37.141 48.379 1.00 60.04 2234 N GLU 537 30.996 38.086 49.970 1.00 60.48 2235 CA GLU 537 31.359 36.838 50.607 1.00 61.60 2236 CB GLU 537 32.691 37.003 51.307 1.00 61.56 2237 CG GLU 537 33.169 35.763 51.998 1.00 58.70 2238 CD GLU 537 34.599 35.907 52.442 1.00 62.52 2239 OE1 GLU 537 35.173 34.900 52.919 1.00 61.18 2240 OE2 GLU 537 35.140 37.033 52.305 1.00 60.21 2241 C GLU 537 30.344 36.288 51.592 1.00 59.30 2242 O GLU 537 30.094 35.084 51.604 1.00 60.22 2243 N VAL 538 29.773 37.155 52.424 1.00 61.88 2244 CA VAL 538 28.781 36.714 53.399 1.00 62.81 2245 CB VAL 538 28.636 37.687 54.591 1.00 57.08 2246 CG1 VAL 538 29.993 38.283 54.957 1.00 61.43 2247 CG2 VAL 538 27.611 38.757 54.268 1.00 60.61 2248 C VAL 538 27.420 36.586 52.752 1.00 61.99 2249 O VAL 538 26.576 35.841 53.233 1.00 61.89 2250 N ILE 539 27.203 37.322 51.669 1.00 61.34 2251 CA ILE 539 25.931 37.263 50.977 1.00 60.88 2252 CB ILE 539 25.628 38.548 50.209 1.00 57.53 2253 CG2 ILE 539 26.034 39.737 51.035 1.00 63.74 2254 CG1 ILE 539 26.365 38.550 48.869 1.00 64.95 2255 CD1 ILE 539 25.847 39.584 47.898 1.00 61.40 2256 C ILE 539 25.946 36.133 49.977 1.00 59.86 2257 O ILE 539 24.984 35.934 49.251 1.00 60.95 2258 N GLU 540 27.051 35.408 49.919 1.00 61.19 2259 CA GLU 540 27.170 34.290 48.993 1.00 64.61 2260 CB GLU 540 28.620 33.798 48.960 1.00 61.89 2261 CG GLU 540 28.917 32.628 48.022 1.00 59.99 2262 CD GLU 540 28.635 32.926 46.560 1.00 60.98 2263 OE1 GLU 540 28.949 34.050 46.103 1.00 60.19 2264 OE2 GLU 540 28.113 32.025 45.861 1.00 58.09 2265 C GLU 540 26.241 33.181 49.469 1.00 60.25 2266 O GLU 540 26.357 32.710 50.603 1.00 62.79 2267 N PRO 541 25.289 32.766 48.614 1.00 59.70 2268 CD PRO 541 24.961 33.287 47.275 1.00 61.01 2269 CA PRO 541 24.362 31.703 49.013 1.00 61.09 2270 CB PRO 541 23.361 31.665 47.861 1.00 63.13 2271 CG PRO 541 24.138 32.177 46.694 1.00 57.00 2272 C PRO 541 25.051 30.365 49.254 1.00 60.83 2273 O PRO 541 25.979 29.988 48.535 1.00 60.28 2274 N GLU 542 24.607 29.669 50.297 1.00 60.82 2275 CA GLU 542 25.157 28.364 50.655 1.00 61.11 2276 CB GLU 542 24.607 27.933 52.001 1.00 63.94 2277 CG GLU 542 23.163 27.558 51.899 1.00 65.51 2278 CD GLU 542 22.569 27.217 53.237 1.00 61.20 2279 OE1 GLU 542 21.369 26.813 53.269 1.00 64.82 2280 OE2 GLU 542 23.307 27.360 54.253 1.00 61.05 2281 C GLU 542 24.668 27.393 49.584 1.00 60.85 2282 O GLU 542 23.631 27.637 48.966 1.00 61.52 2283 N VAL 543 25.369 26.291 49.353 1.00 62.89 2284 CA VAL 543 24.879 25.397 48.316 1.00 61.20 2285 CB VAL 543 26.029 24.589 47.676 1.00 60.15 2286 CG1 VAL 543 27.366 25.164 48.116 1.00 61.25 2287 CG2 VAL 543 25.903 23.132 48.011 1.00 64.25 2288 C VAL 543 23.745 24.465 48.760 1.00 61.19 2289 O VAL 543 23.506 24.232 49.955 1.00 61.59 2290 N LEU 544 23.037 23.944 47.769 1.00 60.75 2291 CA LEU 544 21.910 23.068 48.018 1.00 62.70 2292 CB LEU 544 20.686 23.557 47.244 1.00 61.76 2293 CG LEU 544 20.315 25.041 47.237 1.00 62.21 2294 CD1 LEU 544 19.968 25.490 48.639 1.00 60.39 2295 CD2 LEU 544 21.464 25.856 46.654 1.00 61.37 2296 C LEU 544 22.209 21.639 47.591 1.00 61.62 2297 O LEU 544 23.047 21.388 46.721 1.00 61.82 2298 N TYR 545 21.504 20.713 48.222 1.00 60.41 2299 CA TYR 545 21.623 19.306 47.915 1.00 64.14 2300 CB TYR 545 21.436 18.495 49.189 1.00 59.96 2301 CG TYR 545 22.566 18.713 50.160 1.00 66.69 2302 CD1 TYR 545 22.715 17.908 51.287 1.00 63.31 2303 CE1 TYR 545 23.810 18.056 52.122 1.00 61.54 2304 CD2 TYR 545 23.537 19.684 49.907 1.00 62.21 2305 CE2 TYR 545 24.632 19.843 50.739 1.00 61.49 2306 CZ TYR 545 24.769 19.022 51.842 1.00 59.50 2307 OH TYR 545 25.898 19.142 52.619 1.00 60.93 2308 C TYR 545 20.482 19.111 46.949 1.00 58.64 2309 O TYR 545 19.553 19.912 46.956 1.00 62.56 2310 N ALA 546 20.532 18.077 46.115 1.00 57.51 2311 CA ALA 546 19.461 17.886 45.145 1.00 59.14 2312 CB ALA 546 20.026 17.390 43.845 1.00 60.50 2313 C ALA 546 18.347 16.965 45.595 1.00 62.16 2314 O ALA 546 17.352 16.821 44.895 1.00 62.38 2315 N GLY 547 18.493 16.338 46.755 1.00 59.60 2316 CA GLY 547 17.441 15.445 47.203 1.00 63.46 2317 C GLY 547 17.125 14.408 46.137 1.00 63.02 2318 O GLY 547 15.968 14.068 45.890 1.00 60.60 2319 N TYR 548 18.180 13.918 45.496 1.00 62.10 2320 CA TYR 548 18.095 12.906 44.447 1.00 60.16 2321 CB TYR 548 19.366 12.971 43.621 1.00 60.58 2322 CG TYR 548 19.357 12.107 42.403 1.00 61.55 2323 CD1 TYR 548 18.522 12.406 41.331 1.00 65.33 2324 CE1 TYR 548 18.550 11.657 40.175 1.00 62.35 2325 CD2 TYR 548 20.218 11.023 42.292 1.00 62.44 2326 CE2 TYR 548 20.251 10.267 41.142 1.00 64.59 2327 CZ TYR 548 19.416 10.594 40.086 1.00 60.42 2328 OH TYR 548 19.467 9.877 38.925 1.00 60.60 2329 C TYR 548 17.979 11.519 45.080 1.00 60.53 2330 O TYR 548 18.584 11.272 46.114 1.00 61.95 2331 N ASP 549 17.227 10.603 44.480 1.00 60.31 2332 CA ASP 549 17.135 9.281 45.088 1.00 60.89 2333 CB ASP 549 16.206 8.359 44.317 1.00 61.64 2334 CG ASP 549 15.653 7.256 45.196 1.00 62.87 2335 OD1 ASP 549 16.437 6.715 45.997 1.00 61.92 2336 OD2 ASP 549 14.446 6.929 45.100 1.00 58.12 2337 C ASP 549 18.525 8.656 45.152 1.00 62.05 2338 O ASP 549 19.176 8.728 46.190 1.00 59.43 2339 N SER 550 18.977 8.052 44.049 1.00 61.36 2340 CA SER 550 20.312 7.425 43.963 1.00 61.16 2341 CB SER 550 21.301 8.127 44.910 1.00 61.33 2342 OG SER 550 22.637 8.055 44.435 1.00 65.58 2343 C SER 550 20.286 5.923 44.268 1.00 62.72 2344 O SER 550 21.025 5.138 43.662 1.00 61.37 2345 N SER 551 19.422 5.543 45.206 1.00 60.55 2346 CA SER 551 19.262 4.155 45.623 1.00 62.47 2347 CB SER 551 18.461 4.092 46.927 1.00 59.78 2348 OG SER 551 17.138 4.551 46.727 1.00 65.75 2349 C SER 551 18.548 3.348 44.544 1.00 61.26 2350 O SER 551 18.187 2.189 44.749 1.00 64.05 2351 N VAL 552 18.349 3.976 43.394 1.00 61.88 2352 CA VAL 552 17.683 3.338 42.268 1.00 61.07 2353 CB VAL 552 16.146 3.536 42.346 1.00 61.01 2354 CG1 VAL 552 15.781 4.362 43.582 1.00 62.13 2355 CG2 VAL 552 15.642 4.194 41.084 1.00 63.59 2356 C VAL 552 18.245 3.935 40.975 1.00 60.74 2357 O VAL 552 18.423 5.151 40.872 1.00 60.94 2358 N PRO 553 18.502 3.085 39.966 1.00 57.88 2359 CD PRO 553 17.755 1.824 39.869 1.00 60.27 2360 CA PRO 553 19.058 3.418 38.648 1.00 60.29 2361 CB PRO 553 18.407 2.387 37.718 1.00 59.38 2362 CG PRO 553 17.208 1.918 38.478 1.00 59.68 2363 C PRO 553 18.933 4.837 38.105 1.00 61.75 2364 O PRO 553 17.864 5.452 38.132 1.00 60.81 2365 N ASP 554 20.055 5.352 37.616 1.00 59.48 2366 CA ASP 554 20.061 6.676 37.032 1.00 59.15 2367 CB ASP 554 21.477 7.212 36.819 1.00 62.17 2368 CG ASP 554 22.222 7.452 38.101 1.00 62.93 2369 OD1 ASP 554 21.591 7.655 39.164 1.00 60.70 2370 OD2 ASP 554 23.467 7.455 38.017 1.00 60.19 2371 C ASP 554 19.433 6.505 35.667 1.00 61.49 2372 O ASP 554 18.898 5.446 35.354 1.00 59.51 2373 N SER 555 19.536 7.557 34.859 1.00 60.31 2374 CA SER 555 19.023 7.601 33.492 1.00 60.74 2375 CB SER 555 17.576 7.113 33.419 1.00 64.15 2376 OG SER 555 16.687 8.099 33.896 1.00 60.71 2377 C SER 555 19.092 9.069 33.108 1.00 61.31 2378 O SER 555 18.776 9.929 33.927 1.00 59.93 2379 N THR 556 19.525 9.358 31.883 1.00 62.16 2380 CA THR 556 19.636 10.742 31.434 1.00 61.52 2381 CB THR 556 19.673 10.857 29.895 1.00 59.01 2382 OG1 THR 556 20.850 10.212 29.391 1.00 60.60 2383 CG2 THR 556 19.677 12.330 29.475 1.00 60.87 2384 C THR 556 18.422 11.505 31.913 1.00 61.95 2385 O THR 556 18.517 12.377 32.788 1.00 60.46 2386 N TRP 557 17.285 11.145 31.318 1.00 60.92 2387 CA TRP 557 15.986 11.734 31.611 1.00 63.76 2388 CB TRP 557 14.864 10.739 31.251 1.00 61.57 2389 CG TRP 557 13.719 10.807 32.225 1.00 57.77 2390 CD2 TRP 557 12.895 11.949 32.491 1.00 60.28 2391 CE2 TRP 557 12.066 11.627 33.595 1.00 61.10 2392 CE3 TRP 557 12.785 13.219 31.911 1.00 57.69 2393 CD1 TRP 557 13.357 9.855 33.145 1.00 63.49 2394 NE1 TRP 557 12.369 10.344 33.974 1.00 60.45 2395 CZ2 TRP 557 11.132 12.535 34.132 1.00 61.64 2396 CZ3 TRP 557 11.857 14.124 32.452 1.00 61.15 2397 CH2 TRP 557 11.045 13.773 33.548 1.00 61.06 2398 C TRP 557 15.816 12.176 33.063 1.00 61.03 2399 O TRP 557 15.546 13.342 33.335 1.00 63.66 2400 N ARG 558 15.972 11.228 33.982 1.00 62.37 2401 CA ARG 558 15.798 11.466 35.413 1.00 63.98 2402 CB ARG 558 15.806 10.116 36.134 1.00 61.30 2403 CG ARG 558 15.389 10.127 37.590 1.00 62.22 2404 CD ARG 558 15.189 8.686 38.070 1.00 59.18 2405 NE ARG 558 16.210 8.204 39.005 1.00 60.75 2406 CZ ARG 558 16.280 8.542 40.294 1.00 62.74 2407 NH1 ARG 558 15.392 9.378 40.820 1.00 65.45 2408 NH2 ARG 558 17.222 8.022 41.074 1.00 61.39 2409 C ARG 558 16.814 12.416 36.056 1.00 63.08 2410 O ARG 558 16.524 13.027 37.085 1.00 62.80 2411 N ILE 559 17.991 12.548 35.451 1.00 63.40 2412 CA ILE 559 19.036 13.423 35.983 1.00 59.67 2413 CB ILE 559 20.459 12.828 35.701 1.00 59.65 2414 CG2 ILE 559 21.437 13.905 35.250 1.00 56.03 2415 CG1 ILE 559 20.982 12.150 36.968 1.00 58.33 2416 CD1 ILE 559 22.212 11.327 36.744 1.00 61.31 2417 C ILE 559 18.939 14.862 35.469 1.00 64.14 2418 O ILE 559 18.843 15.792 36.281 1.00 63.80 2419 N MET 560 18.964 15.060 34.151 1.00 58.15 2420 CA MET 560 18.871 16.419 33.646 1.00 61.08 2421 CB MET 560 18.753 16.460 32.095 1.00 60.65 2422 CG MET 560 20.117 16.352 31.322 1.00 63.74 2423 SD MET 560 20.038 16.357 29.422 1.00 63.49 2424 CE MET 560 21.750 16.939 28.970 1.00 61.12 2425 C MET 560 17.634 17.014 34.325 1.00 63.02 2426 O MET 560 17.666 18.156 34.780 1.00 60.37 2427 N THR 561 16.572 16.217 34.457 1.00 60.33 2428 CA THR 561 15.351 16.677 35.123 1.00 60.71 2429 CB THR 561 14.306 15.540 35.292 1.00 58.90 2430 OG1 THR 561 14.006 14.959 34.025 1.00 60.27 2431 CG2 THR 561 13.019 16.080 35.867 1.00 58.67 2432 C THR 561 15.616 17.259 36.520 1.00 60.71 2433 O THR 561 15.390 18.429 36.747 1.00 62.74 2434 N THR 562 16.111 16.434 37.451 1.00 61.67 2435 CA THR 562 16.387 16.821 38.860 1.00 62.60 2436 CB THR 562 16.914 15.721 39.677 1.00 60.58 2437 OG1 THR 562 18.152 15.292 39.081 1.00 59.96 2438 CG2 THR 562 15.938 14.616 39.802 1.00 62.71 2439 C THR 562 17.487 17.786 39.098 1.00 60.58 2440 O THR 562 17.924 18.032 40.229 1.00 63.25 2441 N LEU 563 17.993 18.325 38.047 1.00 60.71 2442 CA LEU 563 19.148 19.110 38.123 1.00 61.15 2443 CB LEU 563 20.009 18.485 37.164 1.00 61.40 2444 CG LEU 563 21.445 18.268 37.247 1.00 60.76 2445 CD1 LEU 563 21.882 17.094 38.118 1.00 59.56 2446 CD2 LEU 563 21.705 18.012 35.810 1.00 62.29 2447 C LEU 563 18.542 20.350 37.631 1.00 60.18 2448 O LEU 563 19.115 21.393 37.453 1.00 62.51 2449 N ASN 564 17.281 20.194 37.278 1.00 62.12 2450 CA ASN 564 16.596 21.312 36.741 1.00 63.12 2451 CB ASN 564 15.703 20.918 35.651 1.00 63.80 2452 CG ASN 564 16.263 21.124 34.284 1.00 60.00 2453 OD1 ASN 564 17.269 21.801 34.085 1.00 59.72 2454 ND2 ASN 564 15.577 20.559 33.311 1.00 61.08 2455 C ASN 564 15.740 21.719 37.867 1.00 61.56 2456 O ASN 564 15.204 22.818 37.863 1.00 61.14 2457 N MET 565 15.483 20.798 38.768 1.00 63.63 2458 CA MET 565 14.643 21.083 39.872 1.00 60.96 2459 CB MET 565 14.164 19.773 40.504 1.00 61.63 2460 CG MET 565 12.686 19.546 40.369 1.00 65.53 2461 SD MET 565 12.013 20.320 38.903 1.00 61.09 2462 CE MET 565 10.337 20.392 39.357 1.00 60.22 2463 C MET 565 15.560 21.814 40.802 1.00 62.76 2464 O MET 565 15.162 22.713 41.539 1.00 60.13 2465 N LEU 566 16.826 21.447 40.746 1.00 62.63 2466 CA LEU 566 17.794 22.101 41.590 1.00 58.73 2467 CB LEU 566 19.007 21.188 41.764 1.00 59.94 2468 CG LEU 566 20.381 21.435 42.410 1.00 60.09 2469 CD1 LEU 566 21.236 21.209 41.243 1.00 60.52 2470 CD2 LEU 566 20.687 22.805 43.045 1.00 59.08 2471 C LEU 566 18.142 23.418 40.952 1.00 61.33 2472 O LEU 566 18.373 24.398 41.652 1.00 61.14 2473 N GLY 567 18.140 23.461 39.625 1.00 57.88 2474 CA GLY 567 18.436 24.703 38.935 1.00 63.27 2475 C GLY 567 17.469 25.785 39.351 1.00 60.49 2476 O GLY 567 17.854 26.938 39.514 1.00 61.62 2477 N GLY 568 16.206 25.412 39.526 1.00 63.72 2478 CA GLY 568 15.212 26.382 39.936 1.00 60.34 2479 C GLY 568 15.617 27.006 41.256 1.00 60.96 2480 O GLY 568 15.913 28.195 41.332 1.00 61.39 2481 N ARG 569 15.662 26.196 42.302 1.00 59.63 2482 CA ARG 569 16.011 26.692 43.623 1.00 58.74 2483 CB ARG 569 16.143 25.530 44.588 1.00 62.58 2484 CG ARG 569 14.860 24.767 44.719 1.00 61.89 2485 CD ARG 569 14.973 23.794 45.842 1.00 60.95 2486 NE ARG 569 16.047 22.854 45.573 1.00 60.03 2487 CZ ARG 569 16.734 22.229 46.513 1.00 60.68 2488 NH1 ARG 569 16.459 22.447 47.793 1.00 65.06 2489 NH2 ARG 569 17.697 21.391 46.169 1.00 63.36 2490 C ARG 569 17.261 27.538 43.671 1.00 59.59 2491 O ARG 569 17.395 28.397 44.539 1.00 58.49 2492 N GLN 570 18.179 27.299 42.747 1.00 60.12 2493 CA GLN 570 19.417 28.069 42.704 1.00 62.83 2494 CB GLN 570 20.457 27.359 41.852 1.00 64.23 2495 CG GLN 570 21.212 26.254 42.529 1.00 60.55 2496 CD GLN 570 22.345 25.738 41.674 1.00 61.81 2497 OE1 GLN 570 23.046 24.818 42.067 1.00 60.88 2498 NE2 GLN 570 22.533 26.331 40.499 1.00 56.12 2499 C GLN 570 19.195 29.462 42.135 1.00 59.62 2500 O GLN 570 19.872 30.409 42.529 1.00 60.45 2501 N VAL 571 18.273 29.571 41.182 1.00 64.99 2502 CA VAL 571 17.953 30.851 40.576 1.00 62.98 2503 CB VAL 571 17.141 30.653 39.278 1.00 62.20 2504 CG1 VAL 571 16.363 31.906 38.929 1.00 61.93 2505 CG2 VAL 571 18.090 30.312 38.140 1.00 61.13 2506 C VAL 571 17.166 31.658 41.605 1.00 63.93 2507 O VAL 571 17.379 32.865 41.763 1.00 65.46 2508 N ILE 572 16.271 30.981 42.317 1.00 61.03 2509 CA ILE 572 15.483 31.623 43.360 1.00 58.70 2510 CB ILE 572 14.548 30.605 44.045 1.00 66.72 2511 CG2 ILE 572 14.006 31.169 45.350 1.00 58.22 2512 CG1 ILE 572 13.425 30.220 43.081 1.00 61.85 2513 CD1 ILE 572 12.411 29.251 43.663 1.00 61.02 2514 C ILE 572 16.456 32.186 44.390 1.00 59.43 2515 O ILE 572 16.240 33.257 44.948 1.00 61.61 2516 N ALA 573 17.531 31.446 44.628 1.00 62.51 2517 CA ALA 573 18.562 31.844 45.571 1.00 63.19 2518 CB ALA 573 19.467 30.662 45.875 1.00 59.65 2519 C ALA 573 19.390 32.994 45.016 1.00 60.08 2520 O ALA 573 19.853 33.852 45.765 1.00 61.27 2521 N ALA 574 19.573 33.004 43.700 1.00 62.86 2522 CA ALA 574 20.350 34.039 43.027 1.00 62.91 2523 CB ALA 574 20.500 33.690 41.553 1.00 60.40 2524 C ALA 574 19.729 35.426 43.176 1.00 61.54 2525 O ALA 574 20.402 36.441 42.977 1.00 62.14 2526 N VAL 575 18.447 35.461 43.535 1.00 63.11 2527 CA VAL 575 17.721 36.716 43.708 1.00 61.22 2528 CB VAL 575 16.214 36.502 43.529 1.00 61.11 2529 CG1 VAL 575 15.500 37.835 43.568 1.00 63.45 2530 CG2 VAL 575 15.950 35.795 42.218 1.00 55.96 2531 C VAL 575 17.970 37.386 45.063 1.00 61.67 2532 O VAL 575 18.242 38.589 45.119 1.00 61.16 2533 N LYS 576 17.866 36.618 46.148 1.00 63.44 2534 CA LYS 576 18.103 37.169 47.477 1.00 61.90 2535 CB LYS 576 17.913 36.120 48.576 1.00 60.65 2536 CG LYS 576 16.569 35.385 48.633 1.00 62.95 2537 CD LYS 576 16.370 34.812 50.045 1.00 61.64 2538 CE LYS 576 15.453 33.594 50.101 1.00 61.27 2539 NZ LYS 576 16.134 32.288 49.785 1.00 60.24 2540 C LYS 576 19.554 37.616 47.498 1.00 62.75 2541 O LYS 576 19.966 38.384 48.367 1.00 59.51 2542 N TRP 577 20.320 37.103 46.534 1.00 64.04 2543 CA TRP 577 21.741 37.407 46.382 1.00 63.24 2544 CB TRP 577 22.447 36.277 45.610 1.00 61.04 2545 CG TRP 577 23.852 36.613 45.166 1.00 62.92 2546 CD2 TRP 577 24.285 36.919 43.828 1.00 59.92 2547 CE2 TRP 577 25.663 37.212 43.892 1.00 60.22 2548 CE3 TRP 577 23.637 36.978 42.584 1.00 61.13 2549 CD1 TRP 577 24.956 36.729 45.958 1.00 63.10 2550 NE1 TRP 577 26.045 37.088 45.201 1.00 58.91 2551 CZ2 TRP 577 26.411 37.557 42.763 1.00 58.75 2552 CZ3 TRP 577 24.378 37.325 41.461 1.00 63.87 2553 CH2 TRP 577 25.754 37.611 41.559 1.00 60.61 2554 C TRP 577 21.923 38.719 45.634 1.00 60.28 2555 O TRP 577 22.654 39.597 46.083 1.00 61.57 2556 N ALA 578 21.251 38.837 44.490 1.00 60.75 2557 CA ALA 578 21.338 40.032 43.661 1.00 62.79 2558 CB ALA 578 20.522 39.847 42.395 1.00 63.55 2559 C ALA 578 20.869 41.274 44.409 1.00 60.84 2560 O ALA 578 21.347 42.370 44.156 1.00 60.70 2561 N LYS 579 19.937 41.105 45.339 1.00 62.74 2562 CA LYS 579 19.423 42.234 46.107 1.00 60.13 2563 CB LYS 579 18.016 41.900 46.640 1.00 60.85 2564 CG LYS 579 16.969 41.709 45.532 1.00 61.81 2565 CD LYS 579 15.725 40.942 45.986 1.00 61.28 2566 CE LYS 579 14.910 41.704 47.020 1.00 61.64 2567 NZ LYS 579 13.708 40.953 47.492 1.00 62.20 2568 C LYS 579 20.372 42.613 47.252 1.00 60.67 2569 O LYS 579 20.251 43.683 47.835 1.00 59.96 2570 N ALA 580 21.322 41.738 47.564 1.00 59.98 2571 CA ALA 580 22.288 42.011 48.630 1.00 60.27 2572 CB ALA 580 22.721 40.713 49.304 1.00 64.73 2573 C ALA 580 23.505 42.722 48.059 1.00 58.96 2574 O ALA 580 24.349 43.229 48.801 1.00 61.59 2575 N ILE 581 23.590 42.738 46.731 1.00 63.39 2576 CA ILE 581 24.690 43.380 46.030 1.00 60.52 2577 CB ILE 581 24.789 42.908 44.559 1.00 60.74 2578 CG2 ILE 581 25.911 43.650 43.840 1.00 63.37 2579 CG1 ILE 581 25.069 41.409 44.494 1.00 60.26 2580 CD1 ILE 581 24.930 40.862 43.091 1.00 61.59 2581 C ILE 581 24.426 44.873 46.025 1.00 63.62 2582 O ILE 581 23.418 45.329 45.482 1.00 63.59 2583 N PRO 582 25.329 45.655 46.634 1.00 62.76 2584 CD PRO 582 26.596 45.257 47.270 1.00 63.28 2585 CA PRO 582 25.162 47.104 46.681 1.00 64.52 2586 CB PRO 582 26.505 47.589 47.226 1.00 62.45 2587 CG PRO 582 26.934 46.473 48.106 1.00 59.21 2588 C PRO 582 24.882 47.654 45.298 1.00 62.22 2589 O PRO 582 25.518 47.252 44.323 1.00 61.69 2590 N GLY 583 23.913 48.560 45.224 1.00 58.26 2591 CA GLY 583 23.565 49.189 43.965 1.00 59.81 2592 C GLY 583 22.640 48.446 43.028 1.00 61.92 2593 O GLY 583 22.231 49.002 42.024 1.00 58.88 2594 N PHE 584 22.302 47.201 43.327 1.00 62.92 2595 CA PHE 584 21.418 46.459 42.438 1.00 61.83 2596 CB PHE 584 21.563 44.953 42.677 1.00 62.46 2597 CG PHE 584 20.863 44.104 41.650 1.00 57.96 2598 CD1 PHE 584 21.406 43.921 40.390 1.00 63.14 2599 CD2 PHE 584 19.646 43.514 41.938 1.00 62.84 2600 CE1 PHE 584 20.746 43.166 39.437 1.00 61.42 2601 CE2 PHE 584 18.980 42.759 40.991 1.00 60.47 2602 CZ PHE 584 19.533 42.585 39.737 1.00 59.28 2603 C PHE 584 19.958 46.883 42.624 1.00 60.13 2604 O PHE 584 19.210 46.996 41.653 1.00 61.49 2605 N ARG 585 19.561 47.131 43.870 1.00 60.78 2606 CA ARG 585 18.190 47.535 44.160 1.00 63.10 2607 CB ARG 585 17.832 47.252 45.627 1.00 59.03 2608 CG ARG 585 17.716 45.757 45.943 1.00 57.77 2609 CD ARG 585 17.222 45.476 47.365 1.00 61.69 2610 NE ARG 585 15.825 45.858 47.587 1.00 62.10 2611 CZ ARG 585 14.800 45.492 46.817 1.00 62.77 2612 NH1 ARG 585 14.996 44.724 45.744 1.00 60.63 2613 NH2 ARG 585 13.569 45.893 47.126 1.00 59.26 2614 C ARG 585 17.952 48.996 43.843 1.00 59.85 2615 O ARG 585 16.833 49.487 43.965 1.00 61.84 2616 N ASN 586 19.003 49.689 43.424 1.00 60.92 2617 CA ASN 586 18.871 51.094 43.090 1.00 62.56 2618 CB ASN 586 19.987 51.892 43.740 1.00 59.81 2619 CG ASN 586 20.079 51.620 45.218 1.00 62.07 2620 OD1 ASN 586 20.714 50.651 45.641 1.00 62.28 2621 ND2 ASN 586 19.415 52.452 46.018 1.00 56.67 2622 C ASN 586 18.865 51.271 41.592 1.00 63.34 2623 O ASN 586 19.054 52.363 41.068 1.00 60.96 2624 N LEU 587 18.648 50.163 40.907 1.00 62.25 2625 CA LEU 587 18.551 50.166 39.467 1.00 60.33 2626 CB LEU 587 19.304 48.971 38.887 1.00 63.97 2627 CG LEU 587 20.823 49.075 38.847 1.00 59.84 2628 CD1 LEU 587 21.410 47.701 38.948 1.00 62.41 2629 CD2 LEU 587 21.262 49.748 37.572 1.00 64.48 2630 C LEU 587 17.053 50.008 39.259 1.00 61.19 2631 O LEU 587 16.355 49.541 40.164 1.00 61.87 2632 N HIS 588 16.556 50.400 38.090 1.00 63.05 2633 CA HIS 588 15.130 50.288 37.829 1.00 58.93 2634 CB HIS 588 14.797 50.621 36.371 1.00 62.93 2635 CG HIS 588 13.338 50.871 36.131 1.00 61.44 2636 CD2 HIS 588 12.679 51.990 35.745 1.00 61.68 2637 ND1 HIS 588 12.369 49.912 36.344 1.00 59.82 2638 CE1 HIS 588 11.178 50.431 36.101 1.00 59.25 2639 NE2 HIS 588 11.339 51.691 35.736 1.00 58.14 2640 C HIS 588 14.723 48.860 38.128 1.00 61.41 2641 O HIS 588 15.515 47.942 37.948 1.00 59.96 2642 N LEU 589 13.492 48.686 38.598 1.00 59.88 2643 CA LEU 589 12.974 47.370 38.929 1.00 61.54 2644 CB LEU 589 11.602 47.509 39.599 1.00 60.80 2645 CG LEU 589 10.980 46.337 40.367 1.00 62.36 2646 CD1 LEU 589 10.643 45.192 39.424 1.00 59.67 2647 CD2 LEU 589 11.934 45.887 41.449 1.00 61.30 2648 C LEU 589 12.867 46.562 37.640 1.00 60.73 2649 O LEU 589 12.841 45.332 37.667 1.00 59.26 2650 N ASP 590 12.811 47.254 36.507 1.00 62.77 2651 CA ASP 590 12.714 46.574 35.222 1.00 59.61 2652 CB ASP 590 12.172 47.516 34.154 1.00 60.63 2653 CG ASP 590 10.676 47.476 34.060 1.00 60.64 2654 OD1 ASP 590 10.031 47.099 35.060 1.00 66.03 2655 OD2 ASP 590 10.140 47.830 32.989 1.00 62.74 2656 C ASP 590 14.077 46.079 34.801 1.00 64.03 2657 O ASP 590 14.194 45.131 34.020 1.00 61.02 2658 N ASP 591 15.109 46.734 35.319 1.00 61.76 2659 CA ASP 591 16.481 46.364 34.993 1.00 61.72 2660 CB ASP 591 17.425 47.557 35.224 1.00 60.28 2661 CG ASP 591 17.174 48.709 34.250 1.00 66.48 2662 OD1 ASP 591 16.782 48.445 33.092 1.00 56.28 2663 OD2 ASP 591 17.393 49.877 34.639 1.00 63.43 2664 C ASP 591 16.937 45.160 35.813 1.00 60.81 2665 O ASP 591 17.642 44.292 35.306 1.00 61.99 2666 N GLN 592 16.515 45.120 37.075 1.00 59.60 2667 CA GLN 592 16.852 44.035 37.981 1.00 59.54 2668 CB GLN 592 16.145 44.209 39.327 1.00 60.92 2669 CG GLN 592 16.268 45.571 39.962 1.00 63.19 2670 CD GLN 592 15.991 45.536 41.460 1.00 61.96 2671 OE1 GLN 592 15.303 44.641 41.967 1.00 59.41 2672 NE2 GLN 592 16.522 46.518 42.176 1.00 61.73 2673 C GLN 592 16.409 42.711 37.376 1.00 58.77 2674 O GLN 592 17.034 41.668 37.606 1.00 60.09 2675 N MET 593 15.319 42.762 36.611 1.00 61.89 2676 CA MET 593 14.756 41.575 35.977 1.00 60.29 2677 CB MET 593 13.257 41.746 35.768 1.00 61.65 2678 CG MET 593 12.401 41.411 36.969 1.00 61.69 2679 SD MET 593 10.676 41.232 36.456 1.00 62.68 2680 CE MET 593 10.249 42.940 36.274 1.00 60.78 2681 C MET 593 15.388 41.229 34.645 1.00 59.77 2682 O MET 593 15.386 40.068 34.241 1.00 61.16 2683 N THR 594 15.904 42.235 33.948 1.00 59.97 2684 CA THR 594 16.541 42.008 32.655 1.00 61.96 2685 CB THR 594 16.828 43.335 31.932 1.00 61.57 2686 OG1 THR 594 15.726 44.234 32.127 1.00 61.11 2687 CG2 THR 594 17.026 43.086 30.435 1.00 62.41 2688 C THR 594 17.865 41.305 32.902 1.00 63.83 2689 O THR 594 18.184 40.287 32.274 1.00 62.47 2690 N LEU 595 18.634 41.865 33.829 1.00 61.96 2691 CA LEU 595 19.924 41.308 34.184 1.00 62.86 2692 CB LEU 595 20.585 42.172 35.265 1.00 61.42 2693 CG LEU 595 20.937 43.615 34.885 1.00 63.11 2694 CD1 LEU 595 21.680 44.276 36.031 1.00 63.10 2695 CD2 LEU 595 21.791 43.634 33.636 1.00 59.45 2696 C LEU 595 19.784 39.859 34.660 1.00 61.56 2697 O LEU 595 20.438 38.960 34.136 1.00 62.15 2698 N LEU 596 18.920 39.629 35.640 1.00 63.33 2699 CA LEU 596 18.728 38.283 36.156 1.00 61.25 2700 CB LEU 596 17.830 38.313 37.387 1.00 59.50 2701 CG LEU 596 18.518 38.469 38.735 1.00 63.65 2702 CD1 LEU 596 17.484 38.837 39.769 1.00 60.39 2703 CD2 LEU 596 19.232 37.190 39.109 1.00 62.18 2704 C LEU 596 18.159 37.293 35.140 1.00 57.46 2705 O LEU 596 18.306 36.079 35.310 1.00 60.98 2706 N GLN 597 17.507 37.800 34.095 1.00 60.24 2707 CA GLN 597 16.915 36.953 33.055 1.00 59.39 2708 CB GLN 597 15.727 37.660 32.413 1.00 63.86 2709 CG GLN 597 14.431 37.528 33.171 1.00 63.29 2710 CD GLN 597 13.365 38.466 32.648 1.00 58.84 2711 OE1 GLN 597 13.389 38.873 31.484 1.00 61.11 2712 NE2 GLN 597 12.414 38.811 33.505 1.00 60.83 2713 C GLN 597 17.927 36.620 31.973 1.00 60.76 2714 O GLN 597 17.829 35.597 31.302 1.00 63.58 2715 N TYR 598 18.900 37.501 31.806 1.00 59.20 2716 CA TYR 598 19.923 37.315 30.807 1.00 61.48 2717 CB TYR 598 20.378 38.678 30.311 1.00 64.95 2718 CG TYR 598 19.364 39.407 29.466 1.00 59.33 2719 CD1 TYR 598 18.119 38.844 29.177 1.00 59.16 2720 CE1 TYR 598 17.213 39.496 28.344 1.00 62.34 2721 CD2 TYR 598 19.673 40.645 28.903 1.00 58.48 2722 CE2 TYR 598 18.771 41.303 28.067 1.00 61.12 2723 CZ TYR 598 17.551 40.721 27.794 1.00 63.18 2724 OH TYR 598 16.680 41.371 26.960 1.00 63.83 2725 C TYR 598 21.130 36.532 31.320 1.00 63.31 2726 O TYR 598 21.850 35.900 30.550 1.00 62.59 2727 N SER 599 21.356 36.554 32.623 1.00 62.16 2728 CA SER 599 22.511 35.859 33.157 1.00 62.80 2729 CB SER 599 23.420 36.885 33.845 1.00 60.71 2730 OG SER 599 22.660 37.845 34.560 1.00 60.75 2731 C SER 599 22.245 34.678 34.093 1.00 60.81 2732 O SER 599 23.183 34.104 34.636 1.00 57.53 2733 N TRP 600 20.986 34.293 34.272 1.00 62.86 2734 CA TRP 600 20.683 33.187 35.180 1.00 60.85 2735 CB TRP 600 19.186 32.813 35.134 1.00 60.84 2736 CG TRP 600 18.745 32.104 33.887 1.00 61.86 2737 CD2 TRP 600 18.561 30.697 33.726 1.00 61.60 2738 CE2 TRP 600 18.300 30.461 32.362 1.00 64.40 2739 CE3 TRP 600 18.599 29.611 34.602 1.00 59.75 2740 CD1 TRP 600 18.574 32.653 32.650 1.00 60.08 2741 NE1 TRP 600 18.311 31.672 31.724 1.00 59.13 2742 CZ2 TRP 600 18.085 29.182 31.854 1.00 61.82 2743 CZ3 TRP 600 18.383 28.342 34.097 1.00 63.01 2744 CH2 TRP 600 18.131 28.137 32.737 1.00 62.11 2745 C TRP 600 21.523 31.963 34.848 1.00 61.75 2746 O TRP 600 21.973 31.238 35.732 1.00 60.91 2747 N MET 601 21.761 31.749 33.564 1.00 62.84 2748 CA MET 601 22.504 30.591 33.172 1.00 60.19 2749 CB MET 601 22.084 30.133 31.794 1.00 61.93 2750 CG MET 601 22.616 28.786 31.496 1.00 63.07 2751 SD MET 601 21.595 27.427 31.465 1.00 62.35 2752 CE MET 601 22.357 26.773 32.529 1.00 60.74 2753 C MET 601 24.008 30.766 33.243 1.00 61.35 2754 O MET 601 24.732 29.790 33.391 1.00 62.01 2755 N SER 602 24.483 32.002 33.146 1.00 59.64 2756 CA SER 602 25.914 32.253 33.227 1.00 61.85 2757 CB SER 602 26.249 33.637 32.675 1.00 63.12 2758 OG SER 602 27.643 33.887 32.746 1.00 63.90 2759 C SER 602 26.356 32.163 34.684 1.00 63.19 2760 O SER 602 27.478 31.765 34.976 1.00 59.89 2761 N LEU 603 25.452 32.537 35.588 1.00 59.89 2762 CA LEU 603 25.703 32.527 37.027 1.00 63.05 2763 CB LEU 603 24.673 33.413 37.748 1.00 60.06 2764 CG LEU 603 24.752 34.936 37.606 1.00 58.80 2765 CD1 LEU 603 23.591 35.588 38.334 1.00 59.17 2766 CD2 LEU 603 26.051 35.422 38.175 1.00 63.89 2767 C LEU 603 25.624 31.118 37.586 1.00 60.06 2768 O LEU 603 26.337 30.753 38.519 1.00 58.30 2769 N MET 604 24.745 30.323 37.004 1.00 62.50 2770 CA MET 604 24.565 28.967 37.468 1.00 61.20 2771 CB MET 604 23.151 28.541 37.166 1.00 59.34 2772 CG MET 604 22.185 28.879 38.247 1.00 61.83 2773 SD MET 604 22.610 30.141 39.388 1.00 62.09 2774 CE MET 604 22.173 29.285 40.731 1.00 60.68 2775 C MET 604 25.578 28.009 36.879 1.00 61.48 2776 O MET 604 25.989 27.048 37.536 1.00 60.91 2777 N ALA 605 25.988 28.292 35.646 1.00 58.39 2778 CA ALA 605 26.970 27.493 34.943 1.00 62.30 2779 CB ALA 605 26.934 27.812 33.472 1.00 63.55 2780 C ALA 605 28.341 27.820 35.502 1.00 63.47 2781 O ALA 605 29.194 26.944 35.590 1.00 60.63 2782 N PHE 606 28.546 29.082 35.882 1.00 60.75 2783 CA PHE 606 29.832 29.536 36.411 1.00 62.24 2784 CB PHE 606 29.951 31.059 36.300 1.00 65.41 2785 CG PHE 606 31.316 31.606 36.663 1.00 64.45 2786 CD1 PHE 606 32.424 31.375 35.848 1.00 62.88 2787 CD2 PHE 606 31.483 32.388 37.802 1.00 61.45 2788 CE1 PHE 606 33.668 31.919 36.162 1.00 61.89 2789 CE2 PHE 606 32.725 32.931 38.120 1.00 63.04 2790 CZ PHE 606 33.814 32.696 37.296 1.00 66.17 2791 C PHE 606 30.044 29.121 37.851 1.00 64.34 2792 O PHE 606 31.154 28.764 38.234 1.00 61.04 2793 N ALA 607 28.997 29.180 38.661 1.00 59.38 2794 CA ALA 607 29.144 28.771 40.047 1.00 61.90 2795 CB ALA 607 27.953 29.224 40.865 1.00 58.55 2796 C ALA 607 29.269 27.246 40.073 1.00 58.23 2797 O ALA 607 29.912 26.681 40.953 1.00 60.68 2798 N LEU 608 28.656 26.571 39.110 1.00 61.24 2799 CA LEU 608 28.771 25.121 39.086 1.00 60.02 2800 CB LEU 608 27.928 24.526 37.958 1.00 62.86 2801 CG LEU 608 27.703 23.018 37.693 1.00 60.90 2802 CD1 LEU 608 27.926 22.923 36.222 1.00 62.46 2803 CD2 LEU 608 28.630 22.033 38.439 1.00 60.02 2804 C LEU 608 30.240 24.783 38.858 1.00 61.60 2805 O LEU 608 30.758 23.870 39.479 1.00 62.78 2806 N GLY 609 30.917 25.511 37.974 1.00 63.89 2807 CA GLY 609 32.319 25.229 37.746 1.00 60.11 2808 C GLY 609 33.143 25.391 39.018 1.00 61.05 2809 O GLY 609 34.080 24.631 39.266 1.00 62.95 2810 N TRP 610 32.783 26.374 39.838 1.00 62.51 2811 CA TRP 610 33.499 26.652 41.073 1.00 63.33 2812 CB TRP 610 32.917 27.885 41.741 1.00 59.08 2813 CG TRP 610 33.617 28.226 43.008 1.00 60.29 2814 CD2 TRP 610 34.910 28.821 43.127 1.00 61.56 2815 CE2 TRP 610 35.194 28.930 44.501 1.00 59.81 2816 CE3 TRP 610 35.860 29.273 42.200 1.00 57.77 2817 CD1 TRP 610 33.178 28.002 44.279 1.00 61.04 2818 NE1 TRP 610 34.121 28.423 45.183 1.00 63.24 2819 CZ2 TRP 610 36.387 29.472 44.973 1.00 58.16 2820 CZ3 TRP 610 37.048 29.811 42.670 1.00 62.09 2821 CH2 TRP 610 37.301 29.905 44.043 1.00 63.07 2822 C TRP 610 33.516 25.510 42.073 1.00 62.56 2823 O TRP 610 34.554 25.205 42.662 1.00 62.85 2824 N ARG 611 32.360 24.896 42.288 1.00 64.01 2825 CA ARG 611 32.268 23.784 43.222 1.00 61.00 2826 CB ARG 611 30.803 23.396 43.440 1.00 60.82 2827 CG ARG 611 29.973 24.437 44.180 1.00 60.63 2828 CD ARG 611 28.568 23.899 44.480 1.00 63.65 2829 NE ARG 611 27.830 23.608 43.250 1.00 60.05 2830 CZ ARG 611 27.228 24.528 42.498 1.00 61.48 2831 NH1 ARG 611 27.255 25.811 42.853 1.00 62.30 2832 NH2 ARG 611 26.638 24.175 41.365 1.00 62.30 2833 C ARG 611 33.049 22.606 42.648 1.00 64.56 2834 O ARG 611 33.712 21.854 43.373 1.00 59.80 2835 N SER 612 32.971 22.467 41.329 1.00 60.03 2836 CA SER 612 33.664 21.403 40.624 1.00 62.69 2837 CB SER 612 33.312 21.451 39.141 1.00 60.54 2838 OG SER 612 31.976 21.038 38.947 1.00 61.90 2839 C SER 612 35.163 21.542 40.815 1.00 60.18 2840 O SER 612 35.842 20.597 41.209 1.00 62.35 2841 N TYR 613 35.663 22.738 40.538 1.00 59.25 2842 CA TYR 613 37.074 23.058 40.677 1.00 60.56 2843 CB TYR 613 37.265 24.534 40.311 1.00 63.42 2844 CG TYR 613 38.515 25.215 40.829 1.00 66.04 2845 CD1 TYR 613 39.771 24.631 40.692 1.00 61.54 2846 CE1 TYR 613 40.925 25.308 41.091 1.00 59.89 2847 CD2 TYR 613 38.443 26.491 41.384 1.00 61.40 2848 CE2 TYR 613 39.586 27.172 41.782 1.00 60.60 2849 CZ TYR 613 40.823 26.577 41.633 1.00 61.69 2850 OH TYR 613 41.950 27.258 42.022 1.00 57.50 2851 C TYR 613 37.624 22.765 42.074 1.00 61.96 2852 O TYR 613 38.665 22.130 42.219 1.00 62.16 2853 N ARG 614 36.913 23.204 43.102 1.00 65.05 2854 CA ARG 614 37.380 23.004 44.463 1.00 59.34 2855 CB ARG 614 36.724 24.017 45.395 1.00 60.68 2856 CG ARG 614 36.950 25.445 45.007 1.00 63.19 2857 CD ARG 614 36.724 26.354 46.190 1.00 59.94 2858 NE ARG 614 37.945 26.927 46.773 1.00 59.42 2859 CZ ARG 614 39.115 27.068 46.145 1.00 60.26 2860 NH1 ARG 614 40.141 27.628 46.776 1.00 60.62 2861 NH2 ARG 614 39.288 26.619 44.906 1.00 59.69 2862 C ARG 614 37.144 21.620 45.019 1.00 60.75 2863 O ARG 614 37.899 21.144 45.869 1.00 61.95 2864 N GLN 615 36.093 20.967 44.549 1.00 60.97 2865 CA GLN 615 35.780 19.654 45.074 1.00 61.36 2866 CB GLN 615 34.282 19.387 44.957 1.00 59.74 2867 CG GLN 615 33.666 18.942 46.273 1.00 65.30 2868 CD GLN 615 32.416 18.106 46.097 1.00 64.80 2869 OE1 GLN 615 32.019 17.380 47.007 1.00 59.65 2870 NE2 GLN 615 31.787 18.204 44.928 1.00 63.88 2871 C GLN 615 36.547 18.523 44.419 1.00 61.87 2872 O GLN 615 36.984 17.588 45.093 1.00 61.19 2873 N SER 616 36.726 18.615 43.109 1.00 62.69 2874 CA SER 616 37.408 17.559 42.387 1.00 60.64 2875 CB SER 616 36.380 16.632 41.757 1.00 64.46 2876 OG SER 616 35.731 17.299 40.688 1.00 63.47 2877 C SER 616 38.347 18.047 41.298 1.00 59.36 2878 O SER 616 38.444 17.424 40.246 1.00 61.79 2879 N SER 617 39.021 19.163 41.534 1.00 62.74 2880 CA SER 617 39.972 19.681 40.560 1.00 60.01 2881 CB SER 617 41.253 18.847 40.638 1.00 56.86 2882 OG SER 617 41.690 18.714 41.980 1.00 64.58 2883 C SER 617 39.433 19.675 39.119 1.00 62.31 2884 O SER 617 40.099 19.196 38.196 1.00 60.08 2885 N ALA 618 38.230 20.213 38.931 1.00 62.60 2886 CA ALA 618 37.600 20.261 37.612 1.00 62.84 2887 CB ALA 618 38.399 21.165 36.676 1.00 61.64 2888 C ALA 618 37.475 18.866 37.005 1.00 60.94 2889 O ALA 618 37.175 18.725 35.820 1.00 63.12 2890 N ASN 619 37.692 17.836 37.820 1.00 60.02 2891 CA ASN 619 37.610 16.465 37.330 1.00 60.02 2892 CB ASN 619 38.467 15.523 38.178 1.00 61.65 2893 CG ASN 619 39.881 15.426 37.663 1.00 65.19 2894 OD1 ASN 619 40.813 15.986 38.241 1.00 58.62 2895 ND2 ASN 619 40.047 14.729 36.547 1.00 59.93 2896 C ASN 619 36.205 15.922 37.241 1.00 63.97 2897 O ASN 619 35.933 15.005 36.469 1.00 61.24 2898 N LEU 620 35.305 16.487 38.028 1.00 61.46 2899 CA LEU 620 33.925 16.044 37.999 1.00 61.85 2900 CB LEU 620 33.599 15.266 39.271 1.00 63.36 2901 CG LEU 620 34.516 14.087 39.589 1.00 60.08 2902 CD1 LEU 620 33.992 13.354 40.805 1.00 65.17 2903 CD2 LEU 620 34.578 13.145 38.408 1.00 59.21 2904 C LEU 620 33.031 17.266 37.890 1.00 63.79 2905 O LEU 620 33.520 18.400 37.844 1.00 62.56 2906 N LEU 621 31.728 17.022 37.808 1.00 60.88 2907 CA LEU 621 30.757 18.096 37.739 1.00 60.93 2908 CB LEU 621 29.822 17.930 36.545 1.00 59.84 2909 CG LEU 621 30.365 18.564 35.272 1.00 61.52 2910 CD1 LEU 621 29.302 18.516 34.204 1.00 61.79 2911 CD2 LEU 621 30.776 19.998 35.547 1.00 62.82 2912 C LEU 621 30.001 17.973 39.033 1.00 59.84 2913 O LEU 621 29.267 17.009 39.249 1.00 59.39 2914 N CYS 622 30.191 18.952 39.903 1.00 60.82 2915 CA CYS 622 29.562 18.902 41.201 1.00 61.70 2916 CB CYS 622 30.612 19.216 42.276 1.00 61.70 2917 SG CYS 622 32.249 18.417 42.005 1.00 55.72 2918 C CYS 622 28.360 19.822 41.333 1.00 60.92 2919 O CYS 622 28.394 20.777 42.107 1.00 60.85 2920 N PHE 623 27.299 19.518 40.584 1.00 62.83 2921 CA PHE 623 26.057 20.298 40.618 1.00 61.52 2922 CB PHE 623 24.944 19.578 39.827 1.00 63.16 2923 CG PHE 623 25.174 19.562 38.332 1.00 64.30 2924 CD1 PHE 623 25.946 18.565 37.734 1.00 62.97 2925 CD2 PHE 623 24.667 20.580 37.527 1.00 59.44 2926 CE1 PHE 623 26.214 18.585 36.354 1.00 60.51 2927 CE2 PHE 623 24.931 20.607 36.152 1.00 61.00 2928 CZ PHE 623 25.705 19.609 35.566 1.00 58.20 2929 C PHE 623 25.631 20.512 42.074 1.00 62.99 2930 O PHE 623 25.433 21.650 42.520 1.00 59.63 2931 N ALA 624 25.489 19.404 42.798 1.00 60.19 2932 CA ALA 624 25.146 19.426 44.220 1.00 60.71 2933 CB ALA 624 23.953 18.540 44.505 1.00 65.97 2934 C ALA 624 26.384 18.877 44.921 1.00 60.87 2935 O ALA 624 27.278 18.328 44.276 1.00 61.88 2936 N PRO 625 26.467 19.023 46.248 1.00 63.71 2937 CD PRO 625 25.561 19.666 47.207 1.00 59.14 2938 CA PRO 625 27.658 18.496 46.924 1.00 61.58 2939 CB PRO 625 27.528 19.055 48.346 1.00 64.33 2940 CG PRO 625 26.534 20.184 48.212 1.00 61.92 2941 C PRO 625 27.593 16.960 46.904 1.00 61.41 2942 O PRO 625 28.630 16.280 46.869 1.00 60.49 2943 N ASP 626 26.353 16.450 46.913 1.00 61.38 2944 CA ASP 626 26.036 15.016 46.914 1.00 61.12 2945 CB ASP 626 25.050 14.730 48.038 1.00 59.24 2946 CG ASP 626 23.643 15.219 47.706 1.00 60.93 2947 OD1 ASP 626 23.518 16.271 47.036 1.00 62.15 2948 OD2 ASP 626 22.658 14.564 48.112 1.00 64.40 2949 C ASP 626 25.405 14.562 45.587 1.00 62.42 2950 O ASP 626 24.526 13.703 45.568 1.00 60.54 2951 N LEU 627 25.834 15.152 44.483 1.00 60.30 2952 CA LEU 627 25.293 14.792 43.183 1.00 61.38 2953 CB LEU 627 24.007 15.569 42.915 1.00 59.07 2954 CG LEU 627 23.311 15.347 41.573 1.00 62.30 2955 CD1 LEU 627 22.632 13.994 41.525 1.00 59.92 2956 CD2 LEU 627 22.300 16.440 41.381 1.00 64.94 2957 C LEU 627 26.349 15.143 42.152 1.00 59.24 2958 O LEU 627 26.321 16.224 41.550 1.00 60.06 2959 N ILE 628 27.284 14.219 41.958 1.00 59.89 2960 CA ILE 628 28.380 14.422 41.030 1.00 60.40 2961 CB ILE 628 29.729 14.056 41.692 1.00 62.59 2962 CG2 ILE 628 30.850 14.267 40.716 1.00 59.44 2963 CG1 ILE 628 29.990 14.940 42.909 1.00 61.86 2964 CD1 ILE 628 29.045 14.711 44.049 1.00 62.51 2965 C ILE 628 28.234 13.609 39.750 1.00 64.22 2966 O ILE 628 28.028 12.402 39.787 1.00 60.75 2967 N ILE 629 28.323 14.272 38.608 1.00 60.54 2968 CA ILE 629 28.239 13.540 37.370 1.00 62.37 2969 CB ILE 629 28.044 14.470 36.165 1.00 65.41 2970 CG2 ILE 629 28.371 13.733 34.877 1.00 61.37 2971 CG1 ILE 629 26.619 15.024 36.170 1.00 63.05 2972 CD1 ILE 629 25.623 14.193 36.983 1.00 60.63 2973 C ILE 629 29.575 12.839 37.270 1.00 60.22 2974 O ILE 629 30.580 13.454 36.929 1.00 58.35 2975 N ASN 630 29.580 11.556 37.611 1.00 60.04 2976 CA ASN 630 30.776 10.726 37.570 1.00 60.83 2977 CB ASN 630 30.674 9.637 38.632 1.00 62.77 2978 CG ASN 630 29.368 8.868 38.556 1.00 60.79 2979 OD1 ASN 630 29.051 8.248 37.541 1.00 61.32 2980 ND2 ASN 630 28.603 8.908 39.632 1.00 62.90 2981 C ASN 630 30.949 10.085 36.197 1.00 60.61 2982 O ASN 630 30.016 10.041 35.403 1.00 62.50 2983 N GLU 631 32.151 9.592 35.926 1.00 63.77 2984 CA GLU 631 32.472 8.954 34.653 1.00 60.65 2985 CB GLU 631 33.804 8.219 34.786 1.00 62.06 2986 CG GLU 631 34.021 7.046 33.841 1.00 63.14 2987 CD GLU 631 35.255 6.229 34.232 1.00 59.80 2988 OE1 GLU 631 36.349 6.836 34.405 1.00 61.43 2989 OE2 GLU 631 35.122 4.988 34.369 1.00 58.68 2990 C GLU 631 31.381 7.986 34.254 1.00 61.07 2991 O GLU 631 30.879 8.014 33.132 1.00 61.02 2992 N GLN 632 31.011 7.126 35.186 1.00 63.77 2993 CA GLN 632 29.978 6.151 34.916 1.00 61.66 2994 CB GLN 632 29.732 5.285 36.159 1.00 61.41 2995 CG GLN 632 30.936 4.415 36.579 1.00 65.26 2996 CD GLN 632 31.704 3.828 35.393 1.00 64.37 2997 OE1 GLN 632 31.109 3.357 34.420 1.00 60.73 2998 NE2 GLN 632 33.034 3.847 35.480 1.00 59.46 2999 C GLN 632 28.695 6.851 34.466 1.00 61.12 3000 O GLN 632 28.055 6.417 33.512 1.00 62.13 3001 N ARG 633 28.334 7.946 35.134 1.00 59.27 3002 CA ARG 633 27.125 8.682 34.767 1.00 61.29 3003 CB ARG 633 26.821 9.786 35.775 1.00 59.65 3004 CG ARG 633 26.235 9.274 37.069 1.00 62.42 3005 CD ARG 633 25.223 10.258 37.602 1.00 60.12 3006 NE ARG 633 24.486 9.732 38.743 1.00 61.79 3007 CZ ARG 633 24.739 10.038 40.011 1.00 64.89 3008 NH1 ARG 633 25.717 10.878 40.308 1.00 60.64 3009 NH2 ARG 633 24.014 9.501 40.984 1.00 62.92 3010 C ARG 633 27.151 9.274 33.360 1.00 61.86 3011 O ARG 633 26.086 9.401 32.750 1.00 59.63 3012 N MET 634 28.337 9.643 32.855 1.00 64.70 3013 CA MET 634 28.465 10.180 31.497 1.00 60.91 3014 CB MET 634 29.921 10.556 31.189 1.00 59.90 3015 CG MET 634 30.438 11.791 31.950 1.00 60.63 3016 SD MET 634 30.042 13.425 31.192 1.00 60.35 3017 CE MET 634 30.985 14.531 32.251 1.00 64.03 3018 C MET 634 27.956 9.086 30.543 1.00 60.81 3019 O MET 634 28.727 8.350 29.899 1.00 62.71 3020 N THR 635 26.622 8.989 30.531 1.00 62.02 3021 CA THR 635 25.820 8.059 29.738 1.00 62.69 3022 CB THR 635 24.313 8.140 30.124 1.00 62.75 3023 OG1 THR 635 24.150 7.893 31.528 1.00 60.63 3024 CG2 THR 635 23.486 7.141 29.303 1.00 61.43 3025 C THR 635 25.912 8.531 28.307 1.00 61.30 3026 O THR 635 26.510 7.876 27.454 1.00 59.84 3027 N LEU 636 25.315 9.694 28.077 1.00 61.92 3028 CA LEU 636 25.270 10.317 26.765 1.00 60.40 3029 CB LEU 636 23.901 10.968 26.586 1.00 63.75 3030 CG LEU 636 22.679 10.156 26.167 1.00 61.04 3031 CD1 LEU 636 22.623 8.760 26.811 1.00 59.92 3032 CD2 LEU 636 21.476 11.011 26.536 1.00 55.92 3033 C LEU 636 26.347 11.377 26.441 1.00 63.57 3034 O LEU 636 26.834 12.087 27.327 1.00 58.28 3035 N PRO 637 26.754 11.471 25.155 1.00 61.79 3036 CD PRO 637 26.479 10.631 23.987 1.00 63.46 3037 CA PRO 637 27.744 12.476 24.794 1.00 60.89 3038 CB PRO 637 28.363 11.932 23.490 1.00 63.07 3039 CG PRO 637 27.855 10.482 23.398 1.00 62.95 3040 C PRO 637 26.780 13.647 24.551 1.00 61.80 3041 O PRO 637 27.038 14.531 23.736 1.00 60.33 3042 N CYS 638 25.605 13.523 25.193 1.00 63.35 3043 CA CYS 638 24.557 14.549 25.225 1.00 58.89 3044 CB CYS 638 23.122 14.023 25.351 1.00 62.48 3045 SG CYS 638 22.633 12.668 24.333 1.00 61.93 3046 C CYS 638 24.925 14.896 26.642 1.00 59.34 3047 O CYS 638 25.366 16.010 26.968 1.00 61.64 3048 N MET 639 24.773 13.878 27.486 1.00 59.95 3049 CA MET 639 25.094 14.058 28.870 1.00 62.51 3050 CB MET 639 24.794 12.794 29.647 1.00 56.25 3051 CG MET 639 24.597 13.021 31.126 1.00 59.11 3052 SD MET 639 23.446 14.225 31.808 1.00 60.73 3053 CE MET 639 24.286 14.281 33.307 1.00 59.61 3054 C MET 639 26.567 14.451 28.934 1.00 60.92 3055 O MET 639 27.074 14.783 30.000 1.00 59.57 3056 N TYR 640 27.244 14.409 27.782 1.00 60.93 3057 CA TYR 640 28.622 14.866 27.693 1.00 62.32 3058 CB TYR 640 29.585 13.827 27.110 1.00 61.41 3059 CG TYR 640 30.961 14.446 26.910 1.00 62.45 3060 CD1 TYR 640 31.797 14.687 28.006 1.00 59.75 3061 CE1 TYR 640 32.996 15.372 27.862 1.00 59.57 3062 CD2 TYR 640 31.376 14.906 25.651 1.00 59.20 3063 CE2 TYR 640 32.578 15.594 25.495 1.00 64.39 3064 CZ TYR 640 33.381 15.827 26.608 1.00 62.16 3065 OH TYR 640 34.554 16.542 26.485 1.00 62.68 3066 C TYR 640 28.650 16.082 26.764 1.00 60.42 3067 O TYR 640 29.264 17.104 27.075 1.00 62.43 3068 N ASP 641 27.985 15.960 25.619 1.00 63.11 3069 CA ASP 641 27.946 17.029 24.617 1.00 64.46 3070 CB ASP 641 26.821 16.780 23.617 1.00 64.30 3071 CG ASP 641 27.232 17.039 22.196 1.00 61.31 3072 OD1 ASP 641 26.317 17.192 21.353 1.00 59.56 3073 OD2 ASP 641 28.453 17.079 21.917 1.00 63.20 3074 C ASP 641 27.729 18.401 25.222 1.00 61.02 3075 O ASP 641 28.073 19.417 24.617 1.00 60.07 3076 N GLN 642 27.124 18.417 26.406 1.00 63.30 3077 CA GLN 642 26.801 19.653 27.115 1.00 60.83 3078 CB GLN 642 25.298 19.837 27.180 1.00 63.77 3079 CG GLN 642 24.570 18.590 26.781 1.00 59.93 3080 CD GLN 642 24.905 18.192 25.345 1.00 61.47 3081 OE1 GLN 642 24.656 17.063 24.922 1.00 59.50 3082 NE2 GLN 642 25.462 19.135 24.580 1.00 60.78 3083 C GLN 642 27.353 19.664 28.518 1.00 60.90 3084 O GLN 642 27.430 20.714 29.136 1.00 60.17 3085 N CYS 643 27.678 18.497 29.052 1.00 61.78 3086 CA CYS 643 28.291 18.491 30.362 1.00 62.44 3087 CB CYS 643 28.348 17.080 30.963 1.00 66.84 3088 SG CYS 643 27.004 16.704 32.130 1.00 64.90 3089 C CYS 643 29.691 18.976 30.015 1.00 61.39 3090 O CYS 643 30.377 19.587 30.836 1.00 61.37 3091 N LYS 644 30.093 18.726 28.768 1.00 63.75 3092 CA LYS 644 31.415 19.128 28.308 1.00 59.22 3093 CB LYS 644 31.708 18.603 26.889 1.00 57.84 3094 CG LYS 644 31.163 19.462 25.740 1.00 63.56 3095 CD LYS 644 31.637 18.994 24.350 1.00 63.09 3096 CE LYS 644 33.034 19.520 23.983 1.00 63.23 3097 NZ LYS 644 34.141 19.025 24.872 1.00 61.68 3098 C LYS 644 31.560 20.641 28.319 1.00 61.63 3099 O LYS 644 32.672 21.157 28.379 1.00 62.21 3100 N HIS 645 30.444 21.359 28.267 1.00 59.46 3101 CA HIS 645 30.518 22.809 28.261 1.00 61.40 3102 CB HIS 645 29.338 23.380 27.490 1.00 62.01 3103 CG HIS 645 29.548 23.365 26.009 1.00 61.11 3104 CD2 HIS 645 30.591 23.797 25.261 1.00 62.23 3105 ND1 HIS 645 28.628 22.845 25.123 1.00 62.89 3106 CE1 HIS 645 29.097 22.957 23.892 1.00 60.35 3107 NE2 HIS 645 30.285 23.532 23.948 1.00 58.72 3108 C HIS 645 30.626 23.413 29.652 1.00 60.22 3109 O HIS 645 31.097 24.535 29.804 1.00 62.73 3110 N MET 646 30.205 22.672 30.668 1.00 61.99 3111 CA MET 646 30.320 23.173 32.027 1.00 60.02 3112 CB MET 646 29.235 22.574 32.963 1.00 60.39 3113 CG MET 646 27.846 22.502 32.348 1.00 59.13 3114 SD MET 646 26.508 21.807 33.298 1.00 59.17 3115 CE MET 646 25.617 21.251 31.946 1.00 56.97 3116 C MET 646 31.712 22.761 32.539 1.00 61.22 3117 O MET 646 32.329 23.495 33.304 1.00 59.33 3118 N LEU 647 32.207 21.597 32.110 1.00 61.22 3119 CA LEU 647 33.539 21.146 32.526 1.00 59.88 3120 CB LEU 647 33.858 19.754 31.962 1.00 64.23 3121 CG LEU 647 33.205 18.494 32.529 1.00 60.79 3122 CD1 LEU 647 33.267 17.423 31.475 1.00 61.72 3123 CD2 LEU 647 33.901 18.030 33.803 1.00 62.44 3124 C LEU 647 34.571 22.141 31.997 1.00 62.52 3125 O LEU 647 35.664 22.292 32.558 1.00 59.55 3126 N TYR 648 34.220 22.816 30.907 1.00 61.57 3127 CA TYR 648 35.126 23.785 30.320 1.00 63.01 3128 CB TYR 648 34.597 24.318 28.997 1.00 64.69 3129 CG TYR 648 35.477 25.427 28.499 1.00 60.08 3130 CD1 TYR 648 36.741 25.148 27.989 1.00 62.71 3131 CE1 TYR 648 37.617 26.170 27.642 1.00 56.16 3132 CD2 TYR 648 35.104 26.764 28.646 1.00 65.58 3133 CE2 TYR 648 35.974 27.795 28.305 1.00 64.32 3134 CZ TYR 648 37.226 27.490 27.806 1.00 62.44 3135 OH TYR 648 38.097 28.500 27.480 1.00 58.63 3136 C TYR 648 35.380 24.969 31.241 1.00 60.50 3137 O TYR 648 36.510 25.423 31.369 1.00 59.77 3138 N VAL 649 34.331 25.490 31.865 1.00 61.19 3139 CA VAL 649 34.521 26.625 32.754 1.00 62.10 3140 CB VAL 649 33.164 27.231 33.257 1.00 63.18 3141 CG1 VAL 649 32.254 27.546 32.089 1.00 60.09 3142 CG2 VAL 649 32.476 26.282 34.202 1.00 59.25 3143 C VAL 649 35.313 26.111 33.941 1.00 63.47 3144 O VAL 649 36.188 26.791 34.465 1.00 58.78 3145 N SER 650 35.010 24.884 34.340 1.00 61.57 3146 CA SER 650 35.664 24.258 35.471 1.00 62.45 3147 CB SER 650 35.032 22.901 35.727 1.00 63.87 3148 OG SER 650 35.312 22.468 37.037 1.00 57.30 3149 C SER 650 37.152 24.102 35.217 1.00 61.59 3150 O SER 650 37.966 24.254 36.123 1.00 59.77 3151 N SER 651 37.506 23.796 33.977 1.00 61.81 3152 CA SER 651 38.904 23.629 33.615 1.00 59.44 3153 CB SER 651 39.029 23.147 32.175 1.00 61.10 3154 OG SER 651 40.285 23.527 31.635 1.00 62.25 3155 C SER 651 39.638 24.942 33.755 1.00 62.21 3156 O SER 651 40.736 24.994 34.299 1.00 59.39 3157 N GLU 652 39.019 25.998 33.248 1.00 60.68 3158 CA GLU 652 39.590 27.333 33.296 1.00 62.47 3159 CB GLU 652 38.683 28.294 32.534 1.00 62.00 3160 CG GLU 652 38.551 27.905 31.087 1.00 60.93 3161 CD GLU 652 39.896 27.841 30.412 1.00 62.60 3162 OE1 GLU 652 40.389 28.912 29.994 1.00 61.37 3163 OE2 GLU 652 40.466 26.727 30.323 1.00 62.86 3164 C GLU 652 39.803 27.829 34.719 1.00 59.21 3165 O GLU 652 40.843 28.404 35.040 1.00 60.26 3166 N LEU 653 38.812 27.613 35.573 1.00 62.17 3167 CA LEU 653 38.939 28.039 36.949 1.00 61.29 3168 CB LEU 653 37.630 27.816 37.702 1.00 62.27 3169 CG LEU 653 36.539 28.833 37.355 1.00 63.87 3170 CD1 LEU 653 35.239 28.428 38.009 1.00 60.88 3171 CD2 LEU 653 36.969 30.220 37.805 1.00 66.93 3172 C LEU 653 40.065 27.252 37.579 1.00 61.64 3173 O LEU 653 40.705 27.711 38.526 1.00 62.53 3174 N HIS 654 40.316 26.067 37.035 1.00 59.14 3175 CA HIS 654 41.386 25.219 37.534 1.00 63.27 3176 CB HIS 654 41.122 23.768 37.166 1.00 63.36 3177 CG HIS 654 42.203 22.842 37.610 1.00 63.44 3178 CD2 HIS 654 43.298 22.379 36.965 1.00 60.81 3179 ND1 HIS 654 42.281 22.360 38.898 1.00 62.60 3180 CE1 HIS 654 43.382 21.642 39.027 1.00 56.60 3181 NE2 HIS 654 44.017 21.639 37.870 1.00 63.72 3182 C HIS 654 42.719 25.654 36.928 1.00 61.86 3183 O HIS 654 43.691 25.906 37.636 1.00 63.73 3184 N ARG 655 42.744 25.732 35.605 1.00 62.82 3185 CA ARG 655 43.929 26.133 34.867 1.00 60.68 3186 CB ARG 655 43.559 26.326 33.394 1.00 56.53 3187 CG ARG 655 44.577 27.074 32.574 1.00 62.54 3188 CD ARG 655 43.921 27.870 31.451 1.00 58.99 3189 NE ARG 655 44.865 28.859 30.951 1.00 62.01 3190 CZ ARG 655 46.081 28.544 30.503 1.00 59.65 3191 NH1 ARG 655 46.475 27.269 30.488 1.00 58.86 3192 NH2 ARG 655 46.926 29.491 30.103 1.00 59.91 3193 C ARG 655 44.525 27.419 35.430 1.00 59.56 3194 O ARG 655 45.741 27.524 35.595 1.00 60.27 3195 N LEU 656 43.664 28.389 35.735 1.00 64.27 3196 CA LEU 656 44.102 29.687 36.250 1.00 58.78 3197 CB LEU 656 43.099 30.751 35.833 1.00 62.45 3198 CG LEU 656 43.072 30.957 34.328 1.00 57.52 3199 CD1 LEU 656 41.832 31.704 33.943 1.00 65.67 3200 CD2 LEU 656 44.305 31.714 33.895 1.00 62.85 3201 C LEU 656 44.340 29.761 37.757 1.00 61.09 3202 O LEU 656 44.995 30.688 38.244 1.00 62.48 3203 N GLN 657 43.816 28.783 38.489 1.00 59.08 3204 CA GLN 657 43.979 28.736 39.936 1.00 63.09 3205 CB GLN 657 45.469 28.663 40.307 1.00 58.16 3206 CG GLN 657 46.052 27.250 40.286 1.00 63.46 3207 CD GLN 657 45.307 26.310 41.225 1.00 59.61 3208 OE1 GLN 657 44.607 25.392 40.785 1.00 64.27 3209 NE2 GLN 657 45.442 26.547 42.529 1.00 59.12 3210 C GLN 657 43.335 29.932 40.611 1.00 59.19 3211 O GLN 657 43.926 30.539 41.498 1.00 61.22 3212 N VAL 658 42.113 30.249 40.192 1.00 61.76 3213 CA VAL 658 41.355 31.376 40.734 1.00 61.31 3214 CB VAL 658 39.970 31.503 40.043 1.00 60.50 3215 CG1 VAL 658 39.211 32.664 40.623 1.00 59.45 3216 CG2 VAL 658 40.132 31.716 38.559 1.00 61.37 3217 C VAL 658 41.115 31.283 42.240 1.00 58.30 3218 O VAL 658 40.838 30.208 42.764 1.00 56.60 3219 N SER 659 41.214 32.418 42.928 1.00 60.76 3220 CA SER 659 40.979 32.465 44.369 1.00 59.93 3221 CB SER 659 41.873 33.507 45.047 1.00 59.20 3222 OG SER 659 41.582 34.817 44.608 1.00 62.34 3223 C SER 659 39.518 32.789 44.656 1.00 62.94 3224 O SER 659 38.784 33.247 43.780 1.00 58.10 3225 N TYR 660 39.097 32.563 45.893 1.00 61.68 3226 CA TYR 660 37.720 32.808 46.250 1.00 62.54 3227 CB TYR 660 37.481 32.526 47.717 1.00 64.73 3228 CG TYR 660 36.014 32.432 48.044 1.00 56.73 3229 CD1 TYR 660 35.144 31.742 47.200 1.00 59.62 3230 CE1 TYR 660 33.817 31.568 47.524 1.00 61.29 3231 CD2 TYR 660 35.507 32.957 49.223 1.00 64.06 3232 CE2 TYR 660 34.176 32.789 49.557 1.00 61.23 3233 CZ TYR 660 33.336 32.085 48.705 1.00 60.34 3234 OH TYR 660 32.032 31.840 49.064 1.00 61.17 3235 C TYR 660 37.250 34.204 45.954 1.00 61.20 3236 O TYR 660 36.162 34.383 45.433 1.00 65.37 3237 N GLU 661 38.057 35.199 46.290 1.00 61.50 3238 CA GLU 661 37.657 36.574 46.052 1.00 58.24 3239 CB GLU 661 38.598 37.523 46.765 1.00 64.85 3240 CG GLU 661 38.276 37.577 48.225 1.00 61.43 3241 CD GLU 661 39.283 38.360 48.991 1.00 60.83 3242 OE1 GLU 661 39.961 39.204 48.365 1.00 59.88 3243 OE2 GLU 661 39.387 38.143 50.219 1.00 59.48 3244 C GLU 661 37.548 36.918 44.591 1.00 58.50 3245 O GLU 661 36.573 37.536 44.178 1.00 62.37 3246 N GLU 662 38.529 36.516 43.798 1.00 63.69 3247 CA GLU 662 38.453 36.784 42.374 1.00 59.27 3248 CB GLU 662 39.646 36.158 41.657 1.00 57.91 3249 CG GLU 662 40.974 36.663 42.122 1.00 62.43 3250 CD GLU 662 42.104 35.948 41.436 1.00 62.15 3251 OE1 GLU 662 41.969 34.732 41.223 1.00 57.52 3252 OE2 GLU 662 43.128 36.585 41.119 1.00 61.99 3253 C GLU 662 37.138 36.188 41.831 1.00 61.83 3254 O GLU 662 36.492 36.771 40.963 1.00 63.75 3255 N TYR 663 36.751 35.031 42.361 1.00 59.76 3256 CA TYR 663 35.525 34.336 41.962 1.00 62.22 3257 CB TYR 663 35.439 32.992 42.694 1.00 58.01 3258 CG TYR 663 34.073 32.342 42.676 1.00 62.53 3259 CD1 TYR 663 33.536 31.831 41.499 1.00 60.26 3260 CE1 TYR 663 32.298 31.201 41.495 1.00 62.40 3261 CD2 TYR 663 33.330 32.212 43.850 1.00 58.63 3262 CE2 TYR 663 32.096 31.590 43.855 1.00 62.25 3263 CZ TYR 663 31.587 31.084 42.676 1.00 63.25 3264 OH TYR 663 30.372 30.448 42.682 1.00 62.04 3265 C TYR 663 34.240 35.125 42.228 1.00 61.08 3266 O TYR 663 33.429 35.343 41.322 1.00 58.41 3267 N LEU 664 34.055 35.528 43.480 1.00 60.59 3268 CA LEU 664 32.876 36.270 43.884 1.00 61.06 3269 CB LEU 664 32.976 36.618 45.369 1.00 63.96 3270 CG LEU 664 33.063 35.440 46.343 1.00 63.81 3271 CD1 LEU 664 33.322 35.929 47.750 1.00 60.79 3272 CD2 LEU 664 31.786 34.656 46.283 1.00 58.66 3273 C LEU 664 32.692 37.539 43.057 1.00 62.83 3274 O LEU 664 31.558 37.955 42.812 1.00 59.88 3275 N CYS 665 33.809 38.139 42.632 1.00 59.97 3276 CA CYS 665 33.805 39.365 41.831 1.00 63.59 3277 CB CYS 665 35.167 40.043 41.869 1.00 60.16 3278 SG CYS 665 35.586 40.757 43.441 1.00 62.94 3279 C CYS 665 33.475 39.091 40.388 1.00 60.01 3280 O CYS 665 32.794 39.876 39.735 1.00 57.49 3281 N MET 666 33.997 37.984 39.883 1.00 60.45 3282 CA MET 666 33.752 37.601 38.510 1.00 61.35 3283 CB MET 666 34.733 36.517 38.077 1.00 60.05 3284 CG MET 666 36.156 36.993 37.902 1.00 63.77 3285 SD MET 666 37.274 35.592 37.856 1.00 59.75 3286 CE MET 666 37.139 35.071 36.150 1.00 62.17 3287 C MET 666 32.338 37.078 38.411 1.00 61.52 3288 O MET 666 31.681 37.255 37.388 1.00 60.47 3289 N LYS 667 31.869 36.433 39.475 1.00 61.04 3290 CA LYS 667 30.516 35.898 39.482 1.00 62.69 3291 CB LYS 667 30.261 35.036 40.726 1.00 61.46 3292 CG LYS 667 28.966 34.228 40.671 1.00 59.84 3293 CD LYS 667 28.678 33.497 41.975 1.00 63.25 3294 CE LYS 667 28.483 34.471 43.123 1.00 59.23 3295 NZ LYS 667 27.639 33.891 44.192 1.00 61.97 3296 C LYS 667 29.554 37.066 39.461 1.00 63.05 3297 O LYS 667 28.459 36.945 38.942 1.00 60.65 3298 N THR 668 29.981 38.201 40.011 1.00 61.58 3299 CA THR 668 29.146 39.398 40.061 1.00 60.37 3300 CB THR 668 29.609 40.357 41.149 1.00 59.81 3301 OG1 THR 668 29.776 39.634 42.370 1.00 59.26 3302 CG2 THR 668 28.588 41.442 41.365 1.00 57.52 3303 C THR 668 29.174 40.146 38.746 1.00 60.69 3304 O THR 668 28.184 40.749 38.348 1.00 61.79 3305 N LEU 669 30.320 40.111 38.076 1.00 58.82 3306 CA LEU 669 30.479 40.774 36.786 1.00 60.62 3307 CB LEU 669 31.947 40.863 36.412 1.00 60.70 3308 CG LEU 669 32.673 41.944 37.192 1.00 61.83 3309 CD1 LEU 669 34.131 41.996 36.761 1.00 63.30 3310 CD2 LEU 669 31.981 43.275 36.953 1.00 62.82 3311 C LEU 669 29.736 40.028 35.707 1.00 63.57 3312 O LEU 669 29.574 40.521 34.599 1.00 63.32 3313 N LEU 670 29.303 38.823 36.034 1.00 62.04 3314 CA LEU 670 28.558 38.030 35.087 1.00 64.79 3315 CB LEU 670 28.662 36.542 35.432 1.00 63.41 3316 CG LEU 670 29.983 35.838 35.078 1.00 62.66 3317 CD1 LEU 670 29.918 34.407 35.554 1.00 61.38 3318 CD2 LEU 670 30.239 35.867 33.580 1.00 61.74 3319 C LEU 670 27.111 38.495 35.114 1.00 60.65 3320 O LEU 670 26.405 38.402 34.119 1.00 60.67 3321 N LEU 671 26.673 39.008 36.257 1.00 60.80 3322 CA LEU 671 25.308 39.500 36.386 1.00 60.13 3323 CB LEU 671 24.977 39.756 37.852 1.00 55.83 3324 CG LEU 671 23.636 40.403 38.198 1.00 59.73 3325 CD1 LEU 671 22.495 39.498 37.819 1.00 58.32 3326 CD2 LEU 671 23.606 40.677 39.673 1.00 59.37 3327 C LEU 671 25.178 40.804 35.613 1.00 60.50 3328 O LEU 671 24.076 41.295 35.377 1.00 61.24 3329 N LEU 672 26.320 41.354 35.219 1.00 59.65 3330 CA LEU 672 26.355 42.613 34.492 1.00 62.17 3331 CB LEU 672 27.128 43.650 35.309 1.00 60.10 3332 CG LEU 672 26.917 43.688 36.822 1.00 65.92 3333 CD1 LEU 672 27.728 44.819 37.407 1.00 60.54 3334 CD2 LEU 672 25.460 43.885 37.148 1.00 58.59 3335 C LEU 672 27.027 42.456 33.131 1.00 62.29 3336 O LEU 672 27.489 43.430 32.554 1.00 61.76 3337 N SER 673 27.070 41.237 32.613 1.00 60.43 3338 CA SER 673 27.732 40.980 31.342 1.00 60.60 3339 CB SER 673 28.212 39.538 31.317 1.00 60.81 3340 OG SER 673 27.281 38.718 31.987 1.00 56.49 3341 C SER 673 26.949 41.280 30.074 1.00 60.41 3342 O SER 673 27.542 41.502 29.020 1.00 60.96 3343 N SER 674 25.625 41.267 30.160 1.00 62.26 3344 CA SER 674 24.800 41.565 28.995 1.00 62.20 3345 CB SER 674 24.359 40.281 28.298 1.00 61.34 3346 OG SER 674 23.730 39.420 29.221 1.00 62.88 3347 C SER 674 23.581 42.371 29.402 1.00 60.51 3348 O SER 674 22.904 42.050 30.376 1.00 62.02 3349 N VAL 675 23.321 43.432 28.653 1.00 61.79 3350 CA VAL 675 22.190 44.299 25.911 1.00 61.63 3351 CB VAL 675 22.670 45.712 29.194 1.00 59.56 3352 CG1 VAL 675 23.388 45.748 30.517 1.00 62.21 3353 CG2 VAL 675 23.598 46.164 28.078 1.00 63.23 3354 C VAL 675 21.325 44.320 27.658 1.00 62.05 3355 O VAL 675 21.757 43.861 26.603 1.00 62.28 3356 N PRO 676 20.077 44.817 27.764 1.00 60.51 3357 CD PRO 676 19.330 45.132 28.991 1.00 63.50 3358 CA PRO 676 19.191 44.880 26.593 1.00 62.22 3359 CB PRO 676 17.896 45.494 27.156 1.00 58.53 3360 CG PRO 676 18.322 46.117 28.488 1.00 60.68 3361 C PRO 676 19.839 45.746 25.514 1.00 58.14 3362 O PRO 676 20.824 46.435 25.792 1.00 61.96 3363 N LYS 677 19.309 45.710 24.293 1.00 60.64 3364 CA LYS 677 19.906 46.501 23.215 1.00 59.47 3365 CB LYS 677 19.025 46.521 21.970 1.00 61.69 3366 CG LYS 677 19.782 46.912 20.707 1.00 61.32 3367 CD LYS 677 18.832 47.051 19.514 1.00 61.48 3368 CE LYS 677 19.604 47.129 18.198 1.00 62.13 3369 NZ LYS 677 20.435 45.908 17.952 1.00 60.25 3370 C LYS 677 20.145 47.929 23.686 1.00 59.29 3371 O LYS 677 21.248 48.235 24.158 1.00 63.94 3372 N ASP 678 19.129 48.796 23.580 1.00 61.98 3373 CA ASP 678 19.302 50.178 24.028 1.00 61.19 3374 CB ASP 678 18.178 51.083 23.506 1.00 60.11 3375 CG ASP 678 18.515 52.582 23.647 1.00 60.40 3376 OD1 ASP 678 18.311 53.325 22.652 1.00 60.21 3377 OD2 ASP 678 18.980 53.011 24.745 1.00 61.19 3378 C ASP 678 19.395 50.284 25.558 1.00 61.02 3379 O ASP 678 18.592 50.955 26.210 1.00 61.94 3380 N GLY 679 20.398 49.604 26.108 1.00 58.42 3381 CA GLY 679 20.649 49.605 27.534 1.00 56.97 3382 C GLY 679 19.449 49.444 28.438 1.00 56.85 3383 O GLY 679 18.362 49.031 28.028 1.00 59.44 3384 N LEU 680 19.674 49.788 29.696 1.00 63.29 3385 CA LEU 680 18.655 49.704 30.727 1.00 62.45 3386 CB LEU 680 19.297 49.181 32.017 1.00 64.86 3387 CG LEU 680 20.118 47.895 31.832 1.00 59.84 3388 CD1 LEU 680 20.946 47.595 33.068 1.00 59.62 3389 CD2 LEU 680 19.181 46.760 31.543 1.00 61.01 3390 C LEU 680 18.056 51.090 30.955 1.00 60.58 3391 O LEU 680 18.433 52.063 30.298 1.00 62.60 3392 N LYS 681 17.120 51.174 31.888 1.00 62.27 3393 CA LYS 681 16.486 52.441 32.197 1.00 63.23 3394 CB LYS 681 15.146 52.211 32.901 1.00 59.95 3395 CG LYS 681 14.188 51.417 32.034 1.00 60.87 3396 CD LYS 681 12.837 51.183 32.665 1.00 61.02 3397 CE LYS 681 12.004 50.295 31.740 1.00 64.07 3398 NZ LYS 681 10.616 50.060 32.218 1.00 58.77 3399 C LYS 681 17.414 53.242 33.072 1.00 60.18 3400 O LYS 681 17.373 54.462 33.069 1.00 63.10 3401 N SER 682 18.278 52.554 33.802 1.00 60.92 3402 CA SER 682 19.214 53.240 34.681 1.00 62.50 3403 CB SER 682 18.953 52.786 36.113 1.00 62.86 3404 OG SER 682 17.564 52.589 36.296 1.00 61.69 3405 C SER 682 20.682 52.993 34.272 1.00 58.65 3406 O SER 682 21.558 52.781 35.120 1.00 60.76 3407 N GLN 683 20.924 53.053 32.961 1.00 60.04 3408 CA GLN 683 22.241 52.840 32.348 1.00 61.19 3409 CB GLN 683 22.156 53.127 30.850 1.00 59.58 3410 CG GLN 683 23.397 52.757 30.056 1.00 62.33 3411 CD GLN 683 23.606 51.259 29.955 1.00 62.33 3412 OE1 GLN 683 22.651 50.502 29.759 1.00 62.13 3413 NE2 GLN 683 24.858 50.823 30.065 1.00 61.30 3414 C GLN 683 23.397 53.655 32.934 1.00 61.70 3415 O GLN 683 24.561 53.335 32.719 1.00 62.18 3416 N GLU 684 23.083 54.710 33.666 1.00 64.02 3417 CA GLU 684 24.117 55.539 34.257 1.00 60.92 3418 CB GLU 684 23.541 56.904 34.590 1.00 62.70 3419 CG GLU 684 22.396 56.780 35.574 1.00 62.30 3420 CD GLU 684 21.884 58.112 36.063 1.00 61.33 3421 OE1 GLU 684 21.260 58.120 37.153 1.00 61.85 3422 OE2 GLU 684 22.092 59.135 35.363 1.00 62.66 3423 C GLU 684 24.582 54.867 35.534 1.00 61.21 3424 O GLU 684 25.741 54.979 35.924 1.00 63.65 3425 N LEU 685 23.659 54.181 36.197 1.00 62.46 3426 CA LEU 685 23.992 53.487 37.429 1.00 60.48 3427 CB LEU 685 22.731 53.265 38.269 1.00 62.31 3428 CG LEU 685 22.992 53.036 39.764 1.00 59.19 3429 CD1 LEU 685 23.700 54.245 40.360 1.00 59.86 3430 CD2 LEU 685 21.684 52.795 40.485 1.00 61.02 3431 C LEU 685 24.657 52.148 37.086 1.00 61.95 3432 O LEU 685 25.524 51.662 37.804 1.00 61.31 3433 N PHE 686 24.264 51.566 35.964 1.00 60.07 3434 CA PHE 686 24.832 50.302 35.560 1.00 60.10 3435 CB PHE 686 24.147 49.785 34.311 1.00 61.65 3436 CG PHE 686 24.500 48.372 33.990 1.00 62.45 3437 CD1 PHE 686 24.148 47.352 34.860 1.00 58.40 3438 CD2 PHE 686 25.204 48.057 32.839 1.00 57.88 3439 CE1 PHE 686 24.493 46.038 34.589 1.00 58.59 3440 CE2 PHE 686 25.558 46.741 32.558 1.00 63.31 3441 CZ PHE 686 25.201 45.733 33.433 1.00 61.15 3442 C PHE 686 26.321 50.423 35.287 1.00 61.88 3443 O PHE 686 27.150 49.890 36.038 1.00 60.58 3444 N ASP 687 26.657 51.113 34.199 1.00 62.94 3445 CA ASP 687 28.048 51.291 33.817 1.00 61.00 3446 CB ASP 687 28.171 52.397 32.776 1.00 59.08 3447 CG ASP 687 27.327 52.131 31.555 1.00 63.32 3448 OD1 ASP 687 27.089 50.940 31.271 1.00 59.10 3449 OD2 ASP 687 26.914 53.098 30.875 1.00 63.48 3450 C ASP 687 28.853 51.645 35.051 1.00 60.66 3451 O ASP 687 29.988 51.203 35.213 1.00 60.12 3452 N GLU 688 28.238 52.424 35.934 1.00 62.70 3453 CA GLU 688 28.869 52.872 37.172 1.00 64.06 3454 CB GLU 688 27.967 53.930 37.803 1.00 59.69 3455 CG GLU 688 28.530 54.718 38.963 1.00 60.90 3456 CD GLU 688 27.609 55.883 39.319 1.00 59.61 3457 OE1 GLU 688 27.607 56.905 38.575 1.00 59.94 3458 OE2 GLU 688 26.871 55.765 40.328 1.00 61.24 3459 C GLU 688 29.137 51.726 38.164 1.00 62.60 3460 O GLU 688 30.199 51.659 38.784 1.00 62.63 3461 N ILE 689 28.166 50.833 38.314 1.00 61.42 3462 CA ILE 689 28.296 49.691 39.207 1.00 64.18 3463 CB ILE 689 26.919 49.043 39.453 1.00 57.30 3464 CG2 ILE 689 27.080 47.686 40.125 1.00 62.29 3465 CG1 ILE 689 26.055 49.980 40.297 1.00 63.30 3466 CD1 ILE 689 24.668 49.458 40.545 1.00 63.34 3467 C ILE 689 29.235 48.654 38.590 1.00 62.15 3468 O ILE 689 30.079 48.071 39.276 1.00 59.58 3469 N ARG 690 29.083 48.416 37.290 1.00 63.61 3470 CA ARG 690 29.938 47.455 36.606 1.00 64.65 3471 CB ARG 690 29.619 47.429 35.111 1.00 61.26 3472 CG ARG 690 30.319 46.331 34.331 1.00 60.27 3473 CD ARG 690 29.665 46.159 32.967 1.00 61.69 3474 NE ARG 690 30.153 44.983 32.247 1.00 64.60 3475 CZ ARG 690 31.331 44.907 31.640 1.00 64.30 3476 NH1 ARG 690 32.158 45.946 31.657 1.00 61.69 3477 NH2 ARG 690 31.682 43.793 31.015 1.00 61.35 3478 C ARG 690 31.387 47.863 36.824 1.00 62.11 3479 O ARG 690 32.208 47.070 37.268 1.00 63.96 3480 N MET 691 31.690 49.118 36.521 1.00 58.67 3481 CA MET 691 33.029 49.642 36.689 1.00 62.38 3482 CB MET 691 33.015 51.144 36.408 1.00 63.73 3483 CG MET 691 34.366 51.723 36.003 1.00 63.05 3484 SD MET 691 35.189 50.799 34.661 1.00 60.35 3485 CE MET 691 36.714 50.382 35.462 1.00 57.09 3486 C MET 691 33.533 49.367 38.106 1.00 61.62 3487 O MET 691 34.653 48.907 38.300 1.00 60.31 3488 N THR 692 32.691 49.633 39.095 1.00 61.56 3489 CA THR 692 33.053 49.428 40.490 1.00 59.70 3490 CB THR 692 31.899 49.838 41.404 1.00 61.08 3491 OG1 THR 692 31.493 51.167 41.074 1.00 61.61 3492 CG2 THR 692 32.331 49.794 42.860 1.00 61.81 3493 C THR 692 33.478 47.997 40.837 1.00 61.92 3494 O THR 692 34.349 47.799 41.695 1.00 59.04 3495 N TYR 693 32.850 47.013 40.190 1.00 58.91 3496 CA TYR 693 33.183 45.605 40.419 1.00 59.83 3497 CB TYR 693 31.961 44.711 40.241 1.00 59.81 3498 CG TYR 693 31.053 44.801 41.437 1.00 63.50 3499 CD1 TYR 693 31.565 44.640 42.728 1.00 59.52 3500 CE1 TYR 693 30.757 44.793 43.844 1.00 63.13 3501 CD2 TYR 693 29.703 45.109 41.297 1.00 59.74 3502 CE2 TYR 693 28.892 45.259 42.409 1.00 61.29 3503 CZ TYR 693 29.428 45.101 43.671 1.00 62.95 3504 OH TYR 693 28.625 45.264 44.760 1.00 60.97 3505 C TYR 693 34.310 45.138 39.530 1.00 62.66 3506 O TYR 693 34.856 44.059 39.732 1.00 60.97 3507 N ILE 694 34.648 45.955 38.536 1.00 62.91 3508 CA ILE 694 35.766 45.651 37.661 1.00 60.76 3509 CB ILE 694 35.726 46.450 36.347 1.00 63.35 3510 CG2 ILE 694 37.057 46.305 35.611 1.00 58.86 3511 CG1 ILE 694 34.570 45.956 35.480 1.00 59.03 3512 CD1 ILE 694 34.524 46.568 34.109 1.00 64.66 3513 C ILE 694 36.947 46.106 38.496 1.00 59.29 3514 O ILE 694 37.976 45.450 38.548 1.00 59.81 3515 N LYS 695 36.788 47.235 39.171 1.00 60.10 3516 CA LYS 695 37.850 47.718 40.031 1.00 59.42 3517 CB LYS 695 37.530 49.111 40.577 1.00 62.71 3518 CG LYS 695 37.525 50.194 39.543 1.00 56.74 3519 CD LYS 695 37.579 51.556 40.199 1.00 62.01 3520 CE LYS 695 37.453 52.666 39.170 1.00 62.05 3521 NZ LYS 695 37.650 54.002 39.778 1.00 58.55 3522 C LYS 695 37.996 46.741 41.193 1.00 60.49 3523 O LYS 695 39.071 46.578 41.744 1.00 58.83 3524 N GLU 696 36.906 46.084 41.559 1.00 58.96 3525 CA GLU 696 36.924 45.135 42.663 1.00 63.14 3526 CB GLU 696 35.489 44.813 43.080 1.00 62.85 3527 CG GLU 696 35.338 44.392 44.513 1.00 61.99 3528 CD GLU 696 35.888 45.410 45.497 1.00 62.60 3529 OE1 GLU 696 35.609 46.616 45.353 1.00 60.89 3530 OE2 GLU 696 36.596 44.999 46.438 1.00 59.40 3531 C GLU 696 37.668 43.855 42.273 1.00 63.03 3532 O GLU 696 38.281 43.198 43.120 1.00 61.00 3533 N LEU 697 37.605 43.507 40.990 1.00 61.52 3534 CA LEU 697 38.279 42.324 40.487 1.00 58.74 3535 CB LEU 697 37.830 42.018 39.057 1.00 58.36 3536 CG LEU 697 38.438 40.757 38.439 1.00 63.54 3537 CD1 LEU 697 37.948 39.560 39.208 1.00 57.14 3538 CD2 LEU 697 38.058 40.623 36.972 1.00 63.58 3539 C LEU 697 39.766 42.633 40.499 1.00 60.87 3540 O LEU 697 40.599 41.748 40.683 1.00 64.34 3541 N GLY 698 40.087 43.907 40.303 1.00 63.62 3542 CA GLY 698 41.472 44.331 40.285 1.00 60.55 3543 C GLY 698 42.053 44.398 41.677 1.00 61.55 3544 O GLY 698 43.259 44.268 41.877 1.00 58.62 3545 N LYS 699 41.180 44.621 42.644 1.00 60.41 3546 CA LYS 699 41.596 44.689 44.027 1.00 61.47 3547 CB LYS 699 40.437 45.189 44.903 1.00 62.58 3548 CG LYS 699 40.251 46.712 44.942 1.00 64.44 3549 CD LYS 699 39.111 47.088 45.889 1.00 59.70 3550 CE LYS 699 39.375 48.368 46.707 1.00 60.92 3551 NZ LYS 699 38.986 49.663 46.056 1.00 62.69 3552 C LYS 699 42.000 43.284 44.447 1.00 64.59 3553 O LYS 699 43.044 43.077 45.063 1.00 59.56 3554 N ALA 700 41.161 42.322 44.080 1.00 58.13 3555 CA ALA 700 41.376 40.927 44.415 1.00 62.66 3556 CB ALA 700 40.219 40.103 43.908 1.00 59.89 3557 C ALA 700 42.678 40.387 43.861 1.00 60.42 3558 O ALA 700 43.430 39.743 44.577 1.00 61.59 3559 N ILE 701 42.937 40.662 42.585 1.00 60.42 3560 CA ILE 701 44.141 40.201 41.898 1.00 63.95 3561 CB ILE 701 44.105 40.611 40.416 1.00 61.37 3562 CG2 ILE 701 45.396 40.224 39.742 1.00 65.93 3563 CG1 ILE 701 42.921 39.939 39.717 1.00 60.90 3564 CD1 ILE 701 42.697 40.405 38.275 1.00 59.90 3565 C ILE 701 45.465 40.675 42.514 1.00 61.05 3566 O ILE 701 46.455 39.931 42.518 1.00 62.71 3567 N VAL 702 45.495 41.901 43.030 1.00 64.20 3568 CA VAL 702 46.723 42.409 43.637 1.00 61.51 3569 CB VAL 702 46.690 43.949 43.841 1.00 61.28 3570 CG1 VAL 702 46.285 44.645 42.546 1.00 61.75 3571 CG2 VAL 702 45.753 44.305 44.983 1.00 63.42 3572 C VAL 702 46.964 41.753 44.995 1.00 62.93 3573 O VAL 702 48.101 41.598 45.432 1.00 62.05 3574 N LYS 703 45.894 41.357 45.665 1.00 61.37 3575 CA LYS 703 46.057 40.741 46.967 1.00 62.89 3576 CB LYS 703 44.714 40.683 47.705 1.00 58.24 3577 CG LYS 703 44.851 40.816 49.215 1.00 61.67 3578 CD LYS 703 45.460 39.557 49.830 1.00 63.57 3579 CE LYS 703 46.410 39.869 50.986 1.00 57.61 3580 NZ LYS 703 46.656 38.664 51.838 1.00 61.16 3581 C LYS 703 46.645 39.355 46.776 1.00 60.39 3582 O LYS 703 46.974 38.668 47.731 1.00 61.26 3583 N ARG 704 46.790 38.951 45.523 1.00 62.02 3584 CA ARG 704 47.369 37.649 45.214 1.00 61.58 3585 CB ARG 704 46.408 36.817 44.368 1.00 61.15 3586 CG ARG 704 45.272 36.177 45.112 1.00 66.70 3587 CD ARG 704 44.871 34.956 44.350 1.00 62.98 3588 NE ARG 704 45.731 34.788 43.185 1.00 58.04 3589 CZ ARG 704 45.973 33.619 42.601 1.00 65.26 3590 NH1 ARG 704 45.422 32.513 43.080 1.00 60.05 3591 NH2 ARG 704 46.761 33.552 41.538 1.00 60.69 3592 C ARG 704 48.686 37.792 44.445 1.00 62.07 3593 O ARG 704 49.779 37.725 45.029 1.00 60.23 3594 N GLU 705 48.555 37.997 43.130 1.00 61.20 3595 CA GLU 705 49.686 38.134 42.212 1.00 61.45 3596 CB GLU 705 49.179 38.271 40.776 1.00 59.83 3597 CG GLU 705 49.038 36.941 40.015 1.00 61.58 3598 CD GLU 705 48.539 35.764 40.875 1.00 62.88 3599 OE1 GLU 705 47.511 35.908 41.595 1.00 61.37 3600 OE2 GLU 705 49.181 34.685 40.806 1.00 62.83 3601 C GLU 705 50.601 39.296 42.542 1.00 60.29 3602 O GLU 705 50.212 40.468 42.446 1.00 61.23 3603 N GLY 706 51.832 38.935 42.896 1.00 60.12 3604 CA GLY 706 52.855 39.883 43.288 1.00 62.85 3605 C GLY 706 53.083 41.191 42.556 1.00 58.46 3606 O GLY 706 52.603 42.244 42.991 1.00 60.65 3607 N ASN 707 53.818 41.141 41.449 1.00 62.51 3608 CA ASN 707 54.158 42.366 40.729 1.00 63.30 3609 CB ASN 707 55.516 42.196 40.013 1.00 60.74 3610 CG ASN 707 55.676 40.835 39.356 1.00 60.19 3611 OD1 ASN 707 55.354 39.797 39.950 1.00 59.76 3612 ND2 ASN 707 56.195 40.833 38.128 1.00 59.34 3613 C ASN 707 53.134 42.993 39.792 1.00 59.87 3614 O ASN 707 52.054 42.451 39.569 1.00 63.44 3615 N SER 708 53.501 44.161 39.265 1.00 60.90 3616 CA SER 708 52.647 44.950 38.382 1.00 58.16 3617 CB SER 708 53.218 46.366 38.244 1.00 62.09 3618 OG SER 708 53.403 46.974 39.516 1.00 61.85 3619 C SER 708 52.432 44.354 36.998 1.00 61.28 3620 O SER 708 51.400 44.607 36.372 1.00 58.94 3621 N SER 709 53.393 43.567 36.516 1.00 61.19 3622 CA SER 709 53.266 42.952 35.193 1.00 59.82 3623 CB SER 709 54.650 42.527 34.665 1.00 62.14 3624 OG SER 709 54.658 42.353 33.249 1.00 61.67 3625 C SER 709 52.338 41.743 35.318 1.00 59.05 3626 O SER 709 51.508 41.479 34.442 1.00 63.30 3627 N GLN 710 52.481 41.022 36.426 1.00 63.44 3628 CA GLN 710 51.652 39.851 36.691 1.00 59.41 3629 CB GLN 710 52.289 39.036 37.833 1.00 63.27 3630 CG GLN 710 53.572 38.329 37.354 1.00 60.06 3631 CD GLN 710 54.362 37.611 38.453 1.00 57.38 3632 OE1 GLN 710 53.781 37.012 39.369 1.00 60.97 3633 NE2 GLN 710 55.701 37.647 38.348 1.00 63.13 3634 C GLN 710 50.209 40.281 37.010 1.00 62.98 3635 O GLN 710 49.250 39.584 36.667 1.00 61.41 3636 N ASN 711 50.087 41.451 37.641 1.00 59.07 3637 CA ASN 711 48.815 42.048 38.017 1.00 59.32 3638 CB ASN 711 49.053 43.439 38.610 1.00 62.53 3639 CG ASN 711 49.400 43.398 40.096 1.00 65.70 3640 OD1 ASN 711 49.886 44.388 40.663 1.00 59.52 3641 ND2 ASN 711 49.140 42.259 40.736 1.00 62.62 3642 C ASN 711 47.918 42.167 36.792 1.00 61.19 3643 O ASN 711 46.796 41.644 36.778 1.00 59.41 3644 N TRP 712 48.418 42.850 35.762 1.00 60.32 3645 CA TRP 712 47.660 43.044 34.534 1.00 65.58 3646 CB TRP 712 48.270 44.168 33.711 1.00 59.75 3647 CG TRP 712 48.272 45.426 34.444 1.00 58.80 3648 CD2 TRP 712 47.148 46.271 34.668 1.00 64.37 3649 CE2 TRP 712 47.577 47.322 35.506 1.00 59.23 3650 CE3 TRP 712 45.812 46.240 34.245 1.00 62.90 3651 CD1 TRP 712 49.313 45.976 35.124 1.00 62.87 3652 NE1 TRP 712 48.905 47.118 35.770 1.00 62.24 3653 CZ2 TRP 712 46.719 48.335 35.935 1.00 60.25 3654 CZ3 TRP 712 44.954 47.247 34.672 1.00 61.54 3655 CH2 TRP 712 45.413 48.281 35.511 1.00 58.28 3656 C TRP 712 47.538 41.811 33.663 1.00 61.45 3657 O TRP 712 46.531 41.623 32.992 1.00 63.89 3658 N GLN 713 48.561 40.974 33.646 1.00 62.44 3659 CA GLN 713 48.493 39.778 32.823 1.00 60.84 3660 CB GLN 713 49.865 39.088 32.761 1.00 59.49 3661 CG GLN 713 50.495 39.114 31.371 1.00 61.40 3662 CD GLN 713 49.624 38.414 30.336 1.00 60.98 3663 OE1 GLN 713 49.306 38.980 29.285 1.00 60.97 3664 NE2 GLN 713 49.232 37.173 30.629 1.00 62.19 3665 C GLN 713 47.446 38.847 33.420 1.00 64.17 3666 O GLN 713 46.843 38.037 32.722 1.00 62.77 3667 N ARG 714 47.242 38.993 34.724 1.00 60.50 3668 CA ARG 714 46.276 38.203 35.481 1.00 60.81 3669 CB ARG 714 46.560 38.352 36.978 1.00 61.22 3670 CG ARG 714 45.609 37.613 37.897 1.00 60.90 3671 CD ARG 714 45.858 36.130 37.894 1.00 60.47 3672 NE ARG 714 44.999 35.455 38.858 1.00 60.72 3673 CZ ARG 714 44.777 34.145 38.860 1.00 62.42 3674 NH1 ARG 714 45.358 33.382 37.943 1.00 57.63 3675 NH2 ARG 714 43.967 33.601 39.762 1.00 61.24 3676 C ARG 714 44.877 38.722 35.174 1.00 61.77 3677 O ARG 714 43.930 37.949 35.007 1.00 61.51 3678 N PHE 715 44.765 40.044 35.107 1.00 59.93 3679 CA PHE 715 43.502 40.691 34.809 1.00 62.80 3680 CB PHE 715 43.630 42.203 34.932 1.00 61.91 3681 CG PHE 715 42.335 42.909 34.749 1.00 63.38 3682 CD1 PHE 715 41.340 42.779 35.706 1.00 62.36 3683 CD2 PHE 715 42.062 43.610 33.581 1.00 62.07 3684 CE1 PHE 715 40.091 43.323 35.504 1.00 60.49 3685 CE2 PHE 715 40.815 44.162 33.365 1.00 62.56 3686 CZ PHE 715 39.823 44.017 34.328 1.00 61.44 3687 C PHE 715 43.046 40.353 33.395 1.00 60.17 3688 O PHE 715 41.849 40.288 33.115 1.00 59.69 3689 N TYR 716 44.017 40.157 32.507 1.00 61.56 3690 CA TYR 716 43.749 39.820 31.116 1.00 60.99 3691 CB TYR 716 45.043 39.870 30.297 1.00 62.72 3692 CG TYR 716 44.810 39.609 28.828 1.00 61.29 3693 CD1 TYR 716 44.115 40.530 28.047 1.00 57.90 3694 CE1 TYR 716 43.790 40.253 26.728 1.00 62.63 3695 CD2 TYR 716 45.188 38.399 28.242 1.00 65.06 3696 CE2 TYR 716 44.866 38.111 26.923 1.00 60.30 3697 CZ TYR 716 44.161 39.044 26.172 1.00 62.23 3698 OH TYR 716 43.798 38.768 24.870 1.00 58.39 3699 C TYR 716 43.157 38.419 31.036 1.00 62.09 3700 O TYR 716 42.085 38.213 30.469 1.00 60.05 3701 N GLN 717 43.875 37.460 31.611 1.00 62.41 3702 CA GLN 717 43.449 36.071 31.623 1.00 60.55 3703 CB GLN 717 44.409 35.222 32.465 1.00 59.06 3704 CG GLN 717 45.855 35.166 31.978 1.00 60.27 3705 CD GLN 717 46.758 34.357 32.919 1.00 60.87 3706 OE1 GLN 717 46.844 34.639 34.124 1.00 61.07 3707 NE2 GLN 717 47.437 33.352 32.369 1.00 62.22 3708 C GLN 717 42.048 35.931 32.194 1.00 59.73 3709 O GLN 717 41.156 35.383 31.545 1.00 64.26 3710 N LEU 718 41.867 36.428 33.415 1.00 58.62 3711 CA LEU 718 40.582 36.348 34.101 1.00 60.65 3712 CB LEU 718 40.708 36.899 35.530 1.00 61.42 3713 CG LEU 718 41.661 36.158 36.487 1.00 61.76 3714 CD1 LEU 718 41.717 36.889 37.809 1.00 60.77 3715 CD2 LEU 718 41.210 34.721 36.701 1.00 59.74 3716 C LEU 718 39.427 37.034 33.375 1.00 59.70 3717 O LEU 718 38.330 36.495 33.327 1.00 60.84 3718 N THR 719 39.661 38.211 32.812 1.00 62.09 3719 CA THR 719 38.608 38.925 32.095 1.00 59.89 3720 CB THR 719 38.985 40.387 31.900 1.00 63.01 3721 OG1 THR 719 40.248 40.465 31.237 1.00 63.25 3722 CG2 THR 719 39.087 41.082 33.240 1.00 61.82 3723 C THR 719 38.329 38.291 30.733 1.00 61.35 3724 O THR 719 37.349 38.622 30.062 1.00 61.10 3725 N LYS 720 39.203 37.371 30.341 1.00 62.98 3726 CA LYS 720 39.074 36.651 29.079 1.00 61.71 3727 CB LYS 720 40.460 36.209 28.588 1.00 62.48 3728 CG LYS 720 40.500 35.805 27.128 1.00 58.53 3729 CD LYS 720 40.038 36.972 26.251 1.00 59.89 3730 CE LYS 720 39.616 36.524 24.842 1.00 58.48 3731 NZ LYS 720 38.772 37.570 24.209 1.00 60.64 3732 C LYS 720 38.184 35.430 29.331 1.00 61.74 3733 O LYS 720 37.479 34.962 28.438 1.00 61.10 3734 N LEU 721 38.228 34.923 30.560 1.00 61.01 3735 CA LEU 721 37.417 33.776 30.938 1.00 64.67 3736 CB LEU 721 37.897 33.187 32.268 1.00 59.87 3737 CG LEU 721 37.656 31.707 32.594 1.00 61.04 3738 CD1 LEU 721 37.766 31.549 34.095 1.00 57.32 3739 CD2 LEU 721 36.292 31.224 32.130 1.00 59.37 3740 C LEU 721 35.983 34.277 31.078 1.00 62.25 3741 O LEU 721 35.031 33.533 30.860 1.00 57.52 3742 N LEU 722 35.830 35.540 31.455 1.00 62.01 3743 CA LEU 722 34.503 36.113 31.591 1.00 62.92 3744 CB LEU 722 34.578 37.497 32.246 1.00 61.91 3745 CG LEU 722 34.841 37.559 33.754 1.00 58.92 3746 CD1 LEU 722 34.946 38.986 34.193 1.00 62.12 3747 CD2 LEU 722 33.728 36.876 34.507 1.00 62.52 3748 C LEU 722 33.949 36.226 30.180 1.00 59.20 3749 O LEU 722 32.883 35.697 29.854 1.00 60.43 3750 N ASP 723 34.714 36.911 29.344 1.00 60.22 3751 CA ASP 723 34.379 37.143 27.952 1.00 60.07 3752 CB ASP 723 35.607 37.697 27.248 1.00 59.74 3753 CG ASP 723 35.437 39.115 26.832 1.00 60.94 3754 OD1 ASP 723 34.869 39.890 27.626 1.00 63.82 3755 OD2 ASP 723 35.883 39.445 25.713 1.00 63.76 3756 C ASP 723 33.909 35.899 27.214 1.00 61.21 3757 O ASP 723 33.108 35.981 26.292 1.00 61.67 3758 N SER 724 34.414 34.743 27.613 1.00 62.19 3759 CA SER 724 34.054 33.521 26.923 1.00 62.38 3760 CB SER 724 35.256 32.578 26.876 1.00 61.26 3761 OG SER 724 35.743 32.308 28.175 1.00 62.27 3762 C SER 724 32.869 32.823 27.539 1.00 63.42 3763 O SER 724 32.419 31.785 27.054 1.00 60.80 3764 N MET 725 32.352 33.395 28.613 1.00 61.24 3765 CA MET 725 31.209 32.794 29.265 1.00 60.73 3766 CB MET 725 30.955 33.461 30.608 1.00 62.85 3767 CG MET 725 30.460 32.506 31.654 1.00 63.01 3768 SD MET 725 31.773 31.403 32.092 1.00 57.07 3769 CE MET 725 30.949 30.380 33.178 1.00 59.44 3770 C MET 725 30.008 32.987 28.352 1.00 59.13 3771 O MET 725 29.022 32.254 28.437 1.00 62.11 3772 N HIS 726 30.105 33.973 27.465 1.00 58.55 3773 CA HIS 726 29.021 34.267 26.547 1.00 60.99 3774 CB HIS 726 29.302 35.554 25.769 1.00 62.45 3775 CG HIS 726 29.036 36.801 26.557 1.00 59.03 3776 CD2 HIS 726 27.909 37.248 27.161 1.00 60.25 3777 ND1 HIS 726 30.003 37.753 26.800 1.00 61.07 3778 CE1 HIS 726 29.484 38.731 27.520 1.00 61.93 3779 NE2 HIS 726 28.215 38.451 27.752 1.00 59.78 3780 C HIS 726 28.773 33.116 25.601 1.00 58.35 3781 O HIS 726 27.638 32.696 25.438 1.00 61.58 3782 N GLU 727 29.816 32.571 24.993 1.00 62.79 3783 CA GLU 727 29.574 31.461 24.086 1.00 60.53 3784 CB GLU 727 30.693 31.307 23.055 1.00 59.90 3785 CG GLU 727 32.005 30.809 23.578 1.00 57.32 3786 CD GLU 727 32.838 30.187 22.473 1.00 59.99 3787 OE1 GLU 727 34.057 30.013 22.680 1.00 62.44 3788 OE2 GLU 727 32.275 29.862 21.400 1.00 63.27 3789 C GLU 727 29.351 30.138 24.791 1.00 59.24 3790 O GLU 727 28.779 29.233 24.203 1.00 62.98 3791 N VAL 728 29.812 29.992 26.029 1.00 60.19 3792 CA VAL 728 29.546 28.732 26.721 1.00 58.29 3793 CB VAL 728 30.493 28.481 27.956 1.00 58.87 3794 CG1 VAL 728 31.261 29.728 28.304 1.00 60.81 3795 CG2 VAL 728 29.694 28.002 29.152 1.00 61.95 3796 C VAL 728 28.082 28.825 27.145 1.00 59.41 3797 O VAL 728 27.335 27.848 27.046 1.00 61.38 3798 N VAL 729 27.670 30.014 27.585 1.00 59.91 3799 CA VAL 729 26.283 30.238 27.971 1.00 60.73 3800 CB VAL 729 26.072 31.664 28.504 1.00 63.53 3801 CG1 VAL 729 24.602 32.062 28.406 1.00 62.52 3802 CG2 VAL 729 26.513 31.725 29.946 1.00 62.40 3803 C VAL 729 25.397 30.004 26.749 1.00 62.11 3804 O VAL 729 24.279 29.493 26.868 1.00 58.35 3805 N GLU 730 25.894 30.372 25.571 1.00 59.30 3806 CA GLU 730 25.133 30.146 24.347 1.00 61.37 3807 CB GLU 730 25.940 30.546 23.125 1.00 57.56 3808 CG GLU 730 25.202 31.467 22.199 1.00 61.79 3809 CD GLU 730 25.875 31.569 20.859 1.00 62.47 3810 OE1 GLU 730 27.039 32.032 20.811 1.00 62.43 3811 OE2 GLU 730 25.235 31.178 19.858 1.00 61.70 3812 C GLU 730 24.832 28.660 24.267 1.00 60.90 3813 O GLU 730 23.701 28.244 24.449 1.00 63.19 3814 N ASN 731 25.864 27.866 24.013 1.00 61.88 3815 CA ASN 731 25.729 26.416 23.919 1.00 63.18 3816 CB ASN 731 27.109 25.761 23.859 1.00 56.96 3817 CG ASN 731 27.516 25.393 22.449 1.00 61.50 3818 OD1 ASN 731 26.909 24.515 21.808 1.00 59.01 3819 ND2 ASN 731 28.552 26.059 21.953 1.00 62.29 3820 C ASN 731 24.927 25.773 25.045 1.00 62.97 3821 O ASN 731 24.251 24.772 24.834 1.00 60.93 3822 N LEU 732 25.002 26.330 26.246 1.00 59.50 3823 CA LEU 732 24.241 25.737 27.326 1.00 57.74 3824 CB LEU 732 24.826 26.120 28.668 1.00 61.00 3825 CG LEU 732 25.964 25.172 29.078 1.00 60.69 3826 CD1 LEU 732 26.278 25.584 30.458 1.00 63.28 3827 CD2 LEU 732 25.589 23.663 29.058 1.00 63.30 3828 C LEU 732 22.761 26.089 27.240 1.00 61.98 3829 O LEU 732 21.912 25.269 27.574 1.00 63.87 3830 N LEU 733 22.456 27.294 26.762 1.00 63.36 3831 CA LEU 733 21.073 27.744 26.596 1.00 57.15 3832 CB LEU 733 21.040 29.241 26.290 1.00 60.30 3833 CG LEU 733 21.134 30.193 27.481 1.00 57.97 3834 CD1 LEU 733 21.471 31.571 26.956 1.00 62.48 3835 CD2 LEU 733 19.824 30.212 28.272 1.00 62.63 3836 C LEU 733 20.354 26.997 25.470 1.00 63.32 3837 O LEU 733 19.256 26.475 25.655 1.00 61.30 3838 N ASN 734 20.965 26.972 24.292 1.00 57.57 3839 CA ASN 734 20.376 26.285 23.159 1.00 59.44 3840 CB ASN 734 21.363 26.277 21.994 1.00 57.94 3841 CG ASN 734 21.671 27.682 21.495 1.00 59.18 3842 OD1 ASN 734 22.072 28.556 22.268 1.00 63.60 3843 ND2 ASN 734 21.476 27.908 20.202 1.00 63.41 3844 C ASN 734 20.038 24.872 23.594 1.00 60.75 3845 O ASN 734 18.904 24.423 23.453 1.00 62.53 3846 N TYR 735 21.017 24.177 24.151 1.00 61.37 3847 CA TYR 735 20.762 22.823 24.597 1.00 58.79 3848 CB TYR 735 22.058 22.201 25.158 1.00 58.40 3849 CG TYR 735 22.087 20.717 24.978 1.00 60.44 3850 CD1 TYR 735 21.309 19.890 25.780 1.00 60.76 3851 CE1 TYR 735 21.240 18.509 25.562 1.00 60.42 3852 CD2 TYR 735 22.815 20.134 23.938 1.00 61.19 3853 CE2 TYR 735 22.750 18.758 23.696 1.00 62.36 3854 CZ TYR 735 21.961 17.950 24.519 1.00 59.04 3855 OH TYR 735 21.899 16.583 24.313 1.00 58.73 3856 C TYR 735 19.649 22.877 25.657 1.00 61.17 3857 O TYR 735 18.858 21.945 25.790 1.00 63.18 3858 N CYS 736 19.574 23.995 26.373 1.00 63.51 3859 CA CYS 736 18.563 24.202 27.403 1.00 65.29 3860 CB CYS 736 18.922 25.433 28.228 1.00 64.15 3861 SG CYS 736 17.642 25.957 29.339 1.00 60.76 3862 C CYS 736 17.183 24.389 26.779 1.00 63.45 3863 O CYS 736 16.251 23.645 27.090 1.00 61.32 3864 N PHE 737 17.061 25.391 25.906 1.00 59.77 3865 CA PHE 737 15.808 25.688 25.209 1.00 61.17 3866 CB PHE 737 16.014 26.792 24.175 1.00 59.61 3867 CG PHE 737 16.348 28.129 24.764 1.00 58.80 3868 CD1 PHE 737 16.060 28.414 26.096 1.00 59.85 3869 CD2 PHE 737 16.924 29.119 23.979 1.00 61.58 3870 CE1 PHE 737 16.340 29.669 26.638 1.00 59.75 3871 CE2 PHE 737 17.207 30.374 24.510 1.00 61.15 3872 CZ PHE 737 16.914 30.649 25.843 1.00 59.90 3873 C PHE 737 15.280 24.462 24.484 1.00 61.86 3874 O PHE 737 14.153 24.024 24.714 1.00 64.04 3875 N GLN 738 16.108 23.932 23.590 1.00 60.57 3876 CA GLN 738 15.786 22.752 22.798 1.00 61.63 3877 CB GLN 738 17.078 22.181 22.220 1.00 62.59 3878 CG GLN 738 16.989 20.805 21.575 1.00 61.50 3879 CD GLN 738 18.368 20.144 21.521 1.00 62.73 3880 OE1 GLN 738 18.581 19.062 22.093 1.00 60.75 3881 NE2 GLN 738 19.321 20.808 20.853 1.00 61.08 3882 C GLN 738 15.043 21.677 23.591 1.00 62.87 3883 O GLN 738 13.970 21.235 23.180 1.00 62.00 3884 N THR 739 15.595 21.262 24.725 1.00 62.54 3885 CA THR 739 14.937 20.228 25.513 1.00 62.00 3886 CB THR 739 15.883 19.572 26.529 1.00 61.40 3887 OG1 THR 739 16.041 20.437 27.659 1.00 59.46 3888 CG2 THR 739 17.234 19.302 25.902 1.00 67.45 3889 C THR 739 13.721 20.740 26.282 1.00 60.54 3890 O THR 739 12.911 19.949 26.758 1.00 60.32 3891 N PHE 740 13.589 22.049 26.433 1.00 60.26 3892 CA PHE 740 12.426 22.572 27.136 1.00 60.59 3893 CB PHE 740 12.645 24.013 27.586 1.00 60.53 3894 CG PHE 740 11.387 24.682 28.073 1.00 60.33 3895 CD1 PHE 740 10.976 24.543 29.399 1.00 60.24 3896 CD2 PHE 740 10.591 25.417 27.196 1.00 60.88 3897 CE1 PHE 740 9.794 25.124 29.842 1.00 62.19 3898 CE2 PHE 740 9.407 26.001 27.629 1.00 63.06 3899 CZ PHE 740 9.005 25.857 28.954 1.00 59.45 3900 C PHE 740 11.269 22.562 26.161 1.00 62.20 3901 O PHE 740 10.102 22.514 26.560 1.00 60.22 3902 N LEU 741 11.619 22.631 24.877 1.00 61.98 3903 CA LEU 741 10.650 22.665 23.783 1.00 61.09 3904 CB LEU 741 11.158 23.561 22.656 1.00 63.24 3905 CG LEU 741 11.286 25.053 22.919 1.00 57.80 3906 CD1 LEU 741 11.680 25.732 21.617 1.00 59.82 3907 CD2 LEU 741 9.966 25.608 23.455 1.00 59.42 3908 C LEU 741 10.313 21.316 23.170 1.00 60.22 3909 O LEU 741 9.748 21.267 22.079 1.00 59.13 3910 N ASP 742 10.662 20.230 23.845 1.00 61.37 3911 CA ASP 742 10.388 18.914 23.309 1.00 61.75 3912 CB ASP 742 11.679 18.315 22.733 1.00 62.29 3913 CG ASP 742 11.476 16.916 22.145 1.00 59.85 3914 OD1 ASP 742 12.450 16.354 21.576 1.00 62.02 3915 OD2 ASP 742 10.348 16.378 22.253 1.00 63.60 3916 C ASP 742 9.843 18.041 24.420 1.00 61.37 3917 O ASP 742 10.614 17.412 25.153 1.00 62.69 3918 N LYS 743 8.517 18.018 24.564 1.00 61.79 3919 CA LYS 743 7.882 17.183 25.595 1.00 58.96 3920 CB LYS 743 6.381 17.501 25.727 1.00 62.19 3921 CG LYS 743 6.056 18.836 26.404 1.00 57.47 3922 CD LYS 743 4.545 19.047 26.473 1.00 59.18 3923 CE LYS 743 4.180 20.313 27.232 1.00 61.36 3924 NZ LYS 743 2.699 20.507 27.295 1.00 57.73 3925 C LYS 743 8.055 15.688 25.281 1.00 61.20 3926 O LYS 743 7.912 14.843 26.165 1.00 60.18 3927 N THR 744 8.366 15.380 24.020 1.00 59.67 3928 CA THR 744 8.580 14.007 23.554 1.00 61.15 3929 CB THR 744 8.792 13.974 22.047 1.00 59.67 3930 OG1 THR 744 7.881 14.890 21.426 1.00 62.19 3931 CG2 THR 744 8.550 12.574 21.513 1.00 63.96 3932 C THR 744 9.818 13.406 24.202 1.00 61.58 3933 O THR 744 9.976 12.195 24.261 1.00 62.58 3934 N MET 745 10.711 14.279 24.646 1.00 57.60 3935 CA MET 745 11.933 13.887 25.334 1.00 62.60 3936 CB MET 745 12.982 14.976 25.147 1.00 59.01 3937 CG MET 745 14.366 14.645 25.612 1.00 60.84 3938 SD MET 745 15.440 15.948 24.965 1.00 58.90 3939 CE MET 745 16.317 15.039 23.610 1.00 62.07 3940 C MET 745 11.435 13.843 26.774 1.00 63.96 3941 O MET 745 11.973 13.137 27.629 1.00 64.77 3942 N SER 746 10.394 14.635 27.025 1.00 59.79 3943 CA SER 746 9.744 14.657 28.326 1.00 60.83 3944 CB SER 746 9.149 13.249 28.576 1.00 61.05 3945 OG SER 746 8.512 13.111 29.842 1.00 61.76 3946 C SER 746 10.597 15.089 29.533 1.00 61.97 3947 O SER 746 10.576 14.408 30.545 1.00 61.88 3948 N ILE 747 11.322 16.207 29.443 1.00 60.50 3949 CA ILE 747 12.140 16.678 30.571 1.00 61.46 3950 CB ILE 747 13.557 17.115 30.098 1.00 57.79 3951 CG2 ILE 747 14.374 17.635 31.275 1.00 62.83 3952 CG1 ILE 747 14.282 15.911 29.484 1.00 61.46 3953 CD1 ILE 747 15.664 16.211 28.976 1.00 65.11 3954 C ILE 747 11.441 17.829 31.318 1.00 63.68 3955 O ILE 747 11.166 18.891 30.747 1.00 62.48 3956 N GLU 748 11.167 17.597 32.601 1.00 59.16 3957 CA GLU 748 10.457 18.546 33.466 1.00 62.34 3958 CB GLU 748 9.803 17.736 34.620 1.00 60.97 3959 CG GLU 748 8.628 18.410 35.400 1.00 63.60 3960 CD GLU 748 7.998 17.505 36.516 1.00 59.56 3961 OE1 GLU 748 8.753 16.918 37.340 1.00 61.60 3962 OE2 GLU 748 6.744 17.396 36.574 1.00 62.18 3963 C GLU 748 11.333 19.701 34.022 1.00 59.89 3964 O GLU 748 12.503 19.498 34.367 1.00 59.20 3965 N PHE 749 10.781 20.913 34.046 1.00 62.20 3966 CA PHE 749 11.484 22.079 34.601 1.00 60.36 3967 CB PHE 749 11.773 23.202 33.571 1.00 63.43 3968 CG PHE 749 12.801 22.827 32.506 1.00 62.31 3969 CD1 PHE 749 12.604 21.790 31.624 1.00 63.18 3970 CD2 PHE 749 13.948 23.639 32.305 1.00 58.27 3971 CE1 PHE 749 13.461 21.555 30.545 1.00 59.47 3972 CE2 PHE 749 14.821 23.409 31.221 1.00 59.31 3973 CZ PHE 749 14.566 22.379 30.341 1.00 60.26 3974 C PHE 749 10.491 22.634 35.646 1.00 57.34 3975 O PHE 749 9.296 22.348 35.598 1.00 62.05 3976 N PRO 750 10.971 23.425 36.612 1.00 61.11 3977 CD PRO 750 12.322 23.572 37.178 1.00 62.36 3978 CA PRO 750 9.955 23.918 37.535 1.00 63.79 3979 CB PRO 750 10.745 24.124 38.834 1.00 59.84 3980 CG PRO 750 12.072 24.510 38.341 1.00 61.92 3981 C PRO 750 9.283 25.174 37.042 1.00 61.44 3982 O PRO 750 9.000 25.325 35.852 1.00 61.38 3983 N GLU 751 9.016 26.087 37.962 1.00 61.10 3984 CA GLU 751 8.375 27.335 37.604 1.00 59.57 3985 CB GLU 751 7.535 27.828 38.778 1.00 60.79 3986 CG GLU 751 6.534 26.804 39.190 1.00 60.87 3987 CD GLU 751 5.716 26.358 38.013 1.00 58.45 3988 OE1 GLU 751 6.004 26.825 36.889 1.00 58.76 3989 OE2 GLU 751 4.768 25.564 38.205 1.00 62.99 3990 C GLU 751 9.449 28.328 37.275 1.00 59.04 3991 O GLU 751 9.644 28.698 36.115 1.00 63.48 3992 N MET 752 10.154 28.736 38.319 1.00 62.70 3993 CA MET 752 11.223 29.693 38.184 1.00 60.75 3994 CB MET 752 12.241 29.499 39.306 1.00 60.00 3995 CG MET 752 13.222 30.641 39.392 1.00 60.74 3996 SD MET 752 12.305 32.203 39.387 1.00 61.02 3997 CE MET 752 12.040 32.394 41.073 1.00 58.25 3998 C MET 752 11.919 29.549 36.847 1.00 61.43 3999 O MET 752 12.062 30.515 36.103 1.00 63.92 4000 N LEU 753 12.329 28.326 36.537 1.00 61.53 4001 CA LEU 753 13.044 28.081 35.307 1.00 63.94 4002 CB LEU 753 13.749 26.729 35.370 1.00 61.07 4003 CG LEU 753 15.278 26.834 35.432 1.00 59.22 4004 CD1 LEU 753 15.720 27.666 36.636 1.00 60.65 4005 CD2 LEU 753 15.870 25.436 35.488 1.00 56.88 4006 C LEU 753 12.182 28.179 34.073 1.00 62.24 4007 O LEU 753 12.539 28.882 33.138 1.00 61.75 4008 N ALA 754 11.049 27.488 34.061 1.00 58.32 4009 CA ALA 754 10.156 27.536 32.902 1.00 60.89 4010 CB ALA 754 8.856 26.790 33.209 1.00 62.87 4011 C ALA 754 9.851 28.995 32.581 1.00 60.33 4012 O ALA 754 10.031 29.471 31.454 1.00 61.42 4013 N GLU 755 9.406 29.698 33.615 1.00 62.19 4014 CA GLU 755 9.040 31.101 33.535 1.00 60.87 4015 CB GLU 755 8.481 31.550 34.891 1.00 60.79 4016 CG GLU 755 7.821 32.911 34.858 1.00 62.93 4017 CD GLU 755 6.333 32.829 35.097 1.00 56.10 4018 OE1 GLU 755 5.741 31.746 34.841 1.00 59.07 4019 OE2 GLU 755 5.761 33.857 35.531 1.00 65.63 4020 C GLU 755 10.163 32.053 33.106 1.00 64.44 4021 O GLU 755 10.006 33.269 33.209 1.00 61.31 4022 N ILE 756 11.296 31.528 32.653 1.00 60.43 4023 CA ILE 756 12.382 32.396 32.187 1.00 58.74 4024 CB ILE 756 13.664 32.292 33.024 1.00 62.34 4025 CG2 ILE 756 14.819 32.942 32.280 1.00 62.52 4026 CG1 ILE 756 13.487 33.000 34.355 1.00 61.56 4027 CD1 ILE 756 14.750 33.012 35.170 1.00 59.91 4028 C ILE 756 12.725 31.933 30.799 1.00 61.14 4029 O ILE 756 12.985 32.732 29.904 1.00 61.35 4030 N ILE 757 12.728 30.618 30.639 1.00 58.95 4031 CA ILE 757 13.026 30.016 29.362 1.00 60.81 4032 CB ILE 757 12.990 28.467 29.480 1.00 60.69 4033 CG2 ILE 757 12.522 27.838 28.197 1.00 64.94 4034 CG1 ILE 757 14.378 27.948 29.883 1.00 60.19 4035 CD1 ILE 757 14.463 27.436 31.313 1.00 62.89 4036 C ILE 757 12.012 30.542 28.348 1.00 59.56 4037 O ILE 757 12.397 30.991 27.276 1.00 61.79 4038 N THR 758 10.726 30.521 28.702 1.00 61.66 4039 CA THR 758 9.677 31.014 27.795 1.00 61.59 4040 CB THR 758 8.224 30.722 28.323 1.00 63.29 4041 OG1 THR 758 8.188 30.811 29.755 1.00 62.91 4042 CG2 THR 758 7.754 29.343 27.874 1.00 61.73 4043 C THR 758 9.809 32.516 27.566 1.00 60.10 4044 O THR 758 9.735 33.002 26.423 1.00 59.44 4045 N ASN 759 10.023 33.242 28.656 1.00 59.76 4046 CA ASN 759 10.154 34.691 28.608 1.00 61.77 4047 CB ASN 759 10.160 35.242 30.034 1.00 62.16 4048 CG ASN 759 9.352 34.371 30.981 1.00 60.61 4049 OD1 ASN 759 9.601 33.164 31.072 1.00 60.73 4050 ND2 ASN 759 8.379 34.965 31.683 1.00 58.61 4051 C ASN 759 11.430 35.091 27.886 1.00 63.83 4052 O ASN 759 11.725 36.278 27.737 1.00 59.18 4053 N GLN 760 12.191 34.099 27.439 1.00 60.77 4054 CA GLN 760 13.431 34.395 26.742 1.00 60.74 4055 CB GLN 760 14.637 34.295 27.690 1.00 63.92 4056 CG GLN 760 14.546 35.101 28.992 1.00 63.35 4057 CD GLN 760 15.114 36.508 28.896 1.00 61.91 4058 OE1 GLN 760 16.231 36.714 28.423 1.00 61.24 4059 NE2 GLN 760 14.351 37.482 29.367 1.00 62.64 4060 C GLN 760 13.687 33.482 25.554 1.00 61.67 4061 O GLN 760 14.390 33.898 24.631 1.00 58.73 4062 N ILE 761 13.124 32.264 25.563 1.00 63.30 4063 CA ILE 761 13.368 31.305 24.476 1.00 62.33 4064 CB ILE 761 12.102 30.454 24.088 1.00 62.35 4065 CG2 ILE 761 12.345 29.721 22.777 1.00 64.29 4066 CG1 ILE 761 11.834 29.367 25.140 1.00 60.68 4067 CD1 ILE 761 12.794 28.186 25.074 1.00 65.98 4068 C ILE 761 13.925 32.069 23.273 1.00 60.92 4069 O ILE 761 15.089 31.875 22.912 1.00 60.54 4070 N PRO 762 13.128 32.938 22.626 1.00 60.85 4071 CD PRO 762 11.810 32.652 22.044 1.00 60.12 4072 CA PRO 762 13.999 33.474 21.571 1.00 60.84 4073 CB PRO 762 13.355 32.980 20.264 1.00 58.66 4074 CG PRO 762 12.240 32.017 20.716 1.00 58.17 4075 C PRO 762 14.222 34.968 21.533 1.00 62.93 4076 O PRO 762 14.168 35.566 20.457 1.00 59.88 4077 N LYS 763 14.405 35.599 22.687 1.00 59.58 4078 CA LYS 763 14.750 37.015 22.653 1.00 62.56 4079 CB LYS 763 14.713 37.645 24.045 1.00 61.84 4080 CG LYS 763 15.014 39.141 24.061 1.00 61.96 4081 CD LYS 763 14.703 39.723 25.430 1.00 62.42 4082 CE LYS 763 13.428 39.096 25.979 1.00 61.00 4083 NZ LYS 763 12.992 39.651 27.285 1.00 62.85 4084 C LYS 763 16.182 36.666 22.292 1.00 58.43 4085 O LYS 763 16.780 37.217 21.354 1.00 59.83 4086 N TYR 764 16.668 35.665 23.036 1.00 59.46 4087 CA TYR 764 17.999 35.106 22.895 1.00 61.50 4088 CB TYR 764 18.291 34.109 24.020 1.00 62.35 4089 CG TYR 764 19.085 34.715 25.149 1.00 57.24 4090 CD1 TYR 764 18.526 34.872 26.424 1.00 62.21 4091 CE1 TYR 764 19.236 35.509 27.451 1.00 63.69 4092 CD2 TYR 764 20.378 35.200 24.927 1.00 62.73 4093 CE2 TYR 764 21.095 35.837 25.942 1.00 62.44 4094 CZ TYR 764 20.516 35.992 27.195 1.00 65.70 4095 OH TYR 764 21.206 36.670 28.168 1.00 63.44 4096 C TYR 764 18.156 34.400 21.570 1.00 60.32 4097 O TYR 764 17.580 34.816 20.556 1.00 60.80 4098 N SER 765 18.922 33.310 21.597 1.00 62.63 4099 CA SER 765 19.209 32.535 20.391 1.00 62.57 4100 CB SER 765 17.908 31.971 19.777 1.00 63.02 4101 OG SER 765 18.172 31.232 18.586 1.00 63.09 4102 C SER 765 19.904 33.487 19.403 1.00 61.20 4103 O SER 765 21.121 33.703 19.474 1.00 60.85 4104 N ASN 766 19.099 34.064 18.513 1.00 59.31 4105 CA ASN 766 19.520 35.005 17.477 1.00 61.38 4106 CB ASN 766 18.344 35.932 17.155 1.00 63.73 4107 CG ASN 766 17.006 35.195 17.116 1.00 60.04 4108 OD1 ASN 766 16.493 34.720 18.153 1.00 64.69 4109 ND2 ASN 766 16.433 35.091 15.916 1.00 59.73 4110 C ASN 766 20.764 35.857 17.800 1.00 64.20 4111 O ASN 766 21.906 35.462 17.491 1.00 60.72 4112 N GLY 767 20.523 37.032 18.396 1.00 59.36 4113 CA GLY 767 21.589 37.961 18.766 1.00 63.17 4114 C GLY 767 21.096 39.388 19.032 1.00 61.77 4115 O GLY 767 21.905 40.321 19.172 1.00 58.54 4116 N ASN 768 19.772 39.550 19.118 1.00 61.70 4117 CA ASN 768 19.115 40.849 19.347 1.00 60.25 4118 CB ASN 768 17.603 40.673 19.163 1.00 61.86 4119 CG ASN 768 17.257 39.882 17.898 1.00 63.48 4120 OD1 ASN 768 17.602 38.702 17.772 1.00 58.87 4121 ND2 ASN 768 16.579 40.534 16.956 1.00 59.56 4122 C ASN 768 19.400 41.566 20.692 1.00 61.21 4123 O ASN 768 18.781 42.595 20.987 1.00 57.65 4124 N ILE 769 20.323 41.011 21.490 1.00 60.01 4125 CA ILE 769 20.764 41.563 22.792 1.00 60.44 4126 CB ILE 769 20.851 40.456 23.891 1.00 60.23 4127 CG2 ILE 769 21.520 41.004 25.161 1.00 65.73 4128 CG1 ILE 769 19.461 39.920 24.234 1.00 64.63 4129 CD1 ILE 769 19.506 38.773 25.256 1.00 63.56 4130 C ILE 769 22.197 42.097 22.594 1.00 60.12 4131 O ILE 769 22.744 41.990 21.495 1.00 59.38 4132 N LYS 770 22.799 42.660 23.643 1.00 58.87 4133 CA LYS 770 24.173 43.171 23.568 1.00 63.22 4134 CB LYS 770 24.210 44.693 23.711 1.00 61.35 4135 CG LYS 770 25.615 45.304 23.656 1.00 60.38 4136 CD LYS 770 25.617 46.682 24.324 1.00 59.38 4137 CE LYS 770 26.765 47.580 23.858 1.00 63.47 4138 NZ LYS 770 26.704 48.946 24.493 1.00 63.76 4139 C LYS 770 25.039 42.568 24.665 1.00 59.00 4140 O LYS 770 24.962 42.967 25.829 1.00 63.74 4141 N LYS 771 25.868 41.604 24.292 1.00 59.72 4142 CA LYS 771 26.742 40.984 25.268 1.00 60.78 4143 CB LYS 771 27.024 39.525 24.871 1.00 59.33 4144 CG LYS 771 27.854 39.345 23.619 1.00 62.03 4145 CD LYS 771 28.351 37.906 23.466 1.00 63.82 4146 CE LYS 771 29.538 37.838 22.501 1.00 59.76 4147 NZ LYS 771 30.301 36.550 22.571 1.00 57.46 4148 C LYS 771 28.044 41.798 25.413 1.00 61.42 4149 O LYS 771 28.800 41.976 24.459 1.00 58.76 4150 N LEU 772 28.271 42.302 26.623 1.00 61.95 4151 CA LEU 772 29.444 43.107 26.948 1.00 60.44 4152 CB LEU 772 29.187 43.864 28.260 1.00 59.38 4153 CG LEU 772 27.923 44.730 28.267 1.00 63.13 4154 CD1 LEU 772 27.630 45.253 29.656 1.00 60.11 4155 CD2 LEU 772 28.102 45.873 27.289 1.00 62.17 4156 C LEU 772 30.732 42.272 27.060 1.00 60.10 4157 O LEU 772 30.764 41.233 27.718 1.00 60.79 4158 N LEU 773 31.797 42.749 26.423 1.00 61.72 4159 CA LEU 773 33.074 42.055 26.428 1.00 60.85 4160 CB LEU 773 33.406 41.580 25.011 1.00 62.82 4161 CG LEU 773 32.425 40.675 24.265 1.00 63.82 4162 CD1 LEU 773 32.927 40.451 22.866 1.00 60.94 4163 CD2 LEU 773 32.285 39.352 24.966 1.00 62.11 4164 C LEU 773 34.205 42.942 26.933 1.00 63.04 4165 O LEU 773 34.271 44.126 26.625 1.00 62.16 4166 N PHE 774 35.101 42.352 27.712 1.00 60.13 4167 CA PHE 774 36.246 43.072 28.248 1.00 61.57 4168 CB PHE 774 36.893 42.279 29.377 1.00 66.09 4169 CG PHE 774 36.280 42.543 30.698 1.00 61.67 4170 CD1 PHE 774 36.524 43.741 31.355 1.00 59.42 4171 CD2 PHE 774 35.385 41.650 31.248 1.00 56.29 4172 CE1 PHE 774 35.879 44.050 32.536 1.00 64.79 4173 CE2 PHE 774 34.729 41.948 32.435 1.00 61.83 4174 CZ PHE 774 34.978 43.155 33.080 1.00 62.07 4175 C PHE 774 37.243 43.261 27.143 1.00 58.09 4176 O PHE 774 38.081 44.155 27.187 1.00 63.24 4177 N HIS 775 37.131 42.398 26.143 1.00 61.71 4178 CA HIS 775 38.022 42.419 25.007 1.00 60.58 4179 CB HIS 775 39.060 41.319 25.175 1.00 63.99 4180 CG HIS 775 39.763 41.365 26.492 1.00 62.38 4181 CD2 HIS 775 39.696 40.548 27.567 1.00 61.52 4182 ND1 HIS 775 40.616 42.389 26.838 1.00 62.48 4183 CE1 HIS 775 41.042 42.202 28.074 1.00 59.32 4184 NE2 HIS 775 40.498 41.092 28.538 1.00 62.24 4185 C HIS 775 37.236 42.196 23.732 1.00 61.77 4186 O HIS 775 36.461 41.252 23.633 1.00 62.62 4187 N GLN 776 37.425 43.083 22.765 1.00 58.75 4188 CA GLN 776 36.759 42.955 21.484 1.00 58.47 4189 CB GLN 776 36.460 44.340 20.893 1.00 58.08 4190 CG GLN 776 37.681 45.247 20.680 1.00 63.95 4191 CD GLN 776 38.236 45.221 19.250 1.00 62.81 4192 OE1 GLN 776 39.158 45.979 18.924 1.00 62.48 4193 NE2 GLN 776 37.680 44.353 18.397 1.00 60.08 4194 C GLN 776 37.724 42.163 20.599 1.00 60.33 4195 O GLN 776 37.269 41.235 19.894 1.00 61.93 4196 OXT GLN 776 38.936 42.474 20.642 1.00 63.26 4197 CB LYS 741 7.500 39.003 28.905 1.00 62.43 4198 CG LYS 741 8.600 39.530 28.004 1.00 60.91 4199 CD LYS 741 9.141 40.875 28.431 1.00 59.52 4200 CE LYS 741 10.182 41.314 27.418 1.00 62.38 4201 NZ LYS 741 10.807 42.617 27.779 1.00 64.43 4202 C LYS 741 6.303 36.975 29.773 1.00 61.31 4203 O LYS 741 6.054 35.766 29.829 1.00 59.09 4204 N LYS 741 6.417 37.458 27.272 1.00 62.30 4205 CA LYS 741 7.109 37.544 28.597 1.00 59.65 4206 N GLU 742 5.905 37.867 30.689 1.00 62.69 4207 CA GLU 742 5.163 37.547 31.917 1.00 61.65 4208 CB GLU 742 4.672 36.083 31.926 1.00 61.06 4209 CG GLU 742 4.087 35.564 33.257 1.00 61.09 4210 CD GLU 742 2.705 36.123 33.568 1.00 62.31 4211 OE1 GLU 742 2.138 35.720 34.616 1.00 57.45 4212 OE2 GLU 742 2.195 36.960 32.771 1.00 60.87 4213 C GLU 742 6.112 37.794 33.099 1.00 63.06 4214 O GLU 742 5.915 38.741 33.853 1.00 61.76 4215 N ASN 743 7.151 36.967 33.238 1.00 63.03 4216 CA ASN 743 8.116 37.101 34.341 1.00 61.82 4217 CB ASN 743 9.276 38.040 33.958 1.00 58.35 4218 CG ASN 743 10.217 37.445 32.909 1.00 59.24 4219 OD1 ASN 743 10.071 37.693 31.699 1.00 60.28 4220 ND2 ASN 743 11.198 36.658 33.372 1.00 60.70 4221 C ASN 743 7.447 37.656 35.604 1.00 61.37 4222 O ASN 743 8.010 38.522 36.284 1.00 60.15 4223 N ALA 744 6.245 37.167 35.907 1.00 60.68 4224 CA ALA 744 5.497 37.626 37.073 1.00 62.31 4225 CB ALA 744 4.024 37.229 36.940 1.00 62.38 4226 C ALA 744 6.080 37.067 38.364 1.00 61.35 4227 O ALA 744 6.168 37.778 39.360 1.00 59.70 4228 N LEU 745 6.490 35.801 38.346 1.00 61.20 4229 CA LEU 745 7.062 35.182 39.538 1.00 59.93 4230 CB LEU 745 7.419 33.710 39.276 1.00 63.15 4231 CG LEU 745 7.255 32.720 40.448 1.00 63.24 4232 CD1 LEU 745 8.022 31.429 40.158 1.00 59.45 4233 CD2 LEU 745 7.759 33.342 41.745 1.00 59.90 4234 C LEU 745 8.313 35.934 39.987 1.00 59.41 4235 O LEU 745 8.520 36.123 41.182 1.00 59.83 4236 N LEU 746 9.137 36.372 39.031 1.00 63.44 4237 CA LEU 746 10.375 37.096 39.350 1.00 60.90 4238 CB LEU 746 11.266 37.239 38.104 1.00 63.43 4239 CG LEU 746 12.771 36.991 38.300 1.00 64.10 4240 CD1 LEU 746 13.540 37.598 37.140 1.00 61.93 4241 CD2 LEU 746 13.248 37.598 39.612 1.00 58.02 4242 C LEU 746 10.120 38.485 39.950 1.00 65.26 4243 O LEU 746 10.649 38.808 41.025 1.00 59.76 4244 N ARG 747 9.334 39.308 39.255 1.00 61.19 4245 CA ARG 747 9.012 40.641 39.762 1.00 61.73 4246 CB ARG 747 7.844 41.256 38.975 1.00 59.04 4247 CG ARG 747 7.475 42.676 39.421 1.00 57.13 4248 CD ARG 747 6.596 43.434 38.407 1.00 58.93 4249 NE ARG 747 7.362 44.324 37.522 1.00 59.01 4250 CZ ARG 747 7.556 44.118 36.221 1.00 59.60 4251 NH1 ARG 747 7.039 43.043 35.624 1.00 63.96 4252 NH2 ARG 747 8.272 44.987 35.518 1.00 60.37 4253 C ARG 747 8.651 40.511 41.247 1.00 61.37 4254 O ARG 747 9.155 41.257 42.090 1.00 62.28 4255 N TYR 748 7.799 39.541 41.565 1.00 62.06 4256 CA TYR 748 7.399 39.306 42.941 1.00 60.54 4257 CB TYR 748 6.517 38.050 43.003 1.00 60.69 4258 CG TYR 748 6.287 37.521 44.401 1.00 59.67 4259 CD1 TYR 748 7.077 36.488 44.908 1.00 60.21 4260 CE1 TYR 748 6.926 36.044 46.209 1.00 60.77 4261 CD2 TYR 748 5.329 38.093 45.240 1.00 63.30 4262 CE2 TYR 748 5.174 37.654 46.550 1.00 61.08 4263 CZ TYR 748 5.977 36.631 47.027 1.00 62.49 4264 OH TYR 748 5.864 36.204 48.331 1.00 59.76 4265 C TYR 748 8.593 39.190 43.908 1.00 63.27 4266 O TYR 748 8.702 39.969 44.857 1.00 60.19 4267 N LEU 749 9.484 38.229 43.663 1.00 62.27 4268 CA LEU 749 10.661 38.008 44.516 1.00 62.12 4269 CB LEU 749 11.454 36.792 44.020 1.00 64.20 4270 CG LEU 749 10.690 35.476 43.873 1.00 58.72 4271 CD1 LEU 749 11.058 34.828 42.554 1.00 61.26 4272 CD2 LEU 749 10.986 34.565 45.039 1.00 61.68 4273 C LEU 749 11.589 39.223 44.561 1.00 61.27 4274 O LEU 749 12.241 39.497 45.571 1.00 60.09 4275 N LEU 750 11.658 39.946 43.455 1.00 60.39 4276 CA LEU 750 12.503 41.120 43.397 1.00 59.95 4277 CB LEU 750 12.603 41.607 41.959 1.00 59.67 4278 CG LEU 750 14.026 41.742 41.404 1.00 65.62 4279 CD1 LEU 750 15.031 40.919 42.205 1.00 61.72 4280 CD2 LEU 750 14.005 41.302 39.953 1.00 61.66 4281 C LEU 750 11.954 42.216 44.298 1.00 58.16 4282 O LEU 750 12.712 42.855 45.032 1.00 61.93 4283 N ASP 751 10.637 42.423 44.242 1.00 60.02 4284 CA ASP 751 9.969 43.428 45.073 1.00 61.63 4285 CB ASP 751 8.539 43.658 44.616 1.00 59.82 4286 CG ASP 751 8.381 44.973 43.912 1.00 60.49 4287 OD1 ASP 751 9.166 45.214 42.968 1.00 59.40 4288 OD2 ASP 751 7.491 45.767 44.298 1.00 59.17 4289 C ASP 751 9.941 43.037 46.531 1.00 62.48 4290 O ASP 751 10.367 43.813 47.383 1.00 63.09 4291 N LYS 752 9.421 41.841 46.808 1.00 64.09 4292 CA LYS 752 9.346 41.308 48.164 1.00 60.89 4293 CB LYS 752 9.881 39.882 48.216 1.00 63.21 4294 CG LYS 752 9.051 38.811 47.568 1.00 57.72 4295 CD LYS 752 9.168 37.532 48.396 1.00 60.58 4296 CE LYS 752 8.769 37.801 49.858 1.00 63.26 4297 NZ LYS 752 8.598 36.571 50.686 1.00 60.07 4298 C LYS 752 10.218 42.123 49.090 1.00 59.75 4299 O LYS 752 11.426 42.228 48.869 1.00 61.26 4300 N ASP 753 9.644 42.700 50.132 1.00 64.75 4301 CA ASP 753 10.478 43.462 51.039 1.00 60.32 4302 CB ASP 753 9.643 44.126 52.126 1.00 62.72 4303 CG ASP 753 10.496 44.762 53.198 1.00 62.87 4304 OD1 ASP 753 11.420 45.549 52.863 1.00 59.14 4305 OD2 ASP 753 10.239 44.468 54.382 1.00 63.19 4306 C ASP 753 11.455 42.468 51.647 1.00 60.33 4307 O ASP 753 12.111 42.750 52.646 1.00 61.12 4308 N ALA 754 11.528 41.304 51.008 1.00 59.93 4309 CA ALA 754 12.396 40.177 51.356 1.00 61.16 4310 CB ALA 754 12.896 39.509 50.053 1.00 64.36 4311 C ALA 754 13.587 40.401 52.307 1.00 59.44 4312 O ALA 754 14.700 39.937 52.047 1.00 61.71 4313 N THR 755 13.355 41.108 53.403 1.00 60.67 4314 CA THR 755 14.375 41.342 54.420 1.00 60.98 4315 CB THR 755 15.250 42.613 54.137 1.00 63.96 4316 OG1 THR 755 14.460 43.794 54.313 1.00 60.28 4317 CG2 THR 755 15.824 42.582 52.696 1.00 57.43 4318 C THR 755 13.505 41.499 55.671 1.00 59.27 4319 O THR 755 13.323 42.586 56.237 1.00 60.51 4320 N ALA 756 12.918 40.356 56.024 1.00 62.21 4321 CA ALA 756 12.025 40.165 57.162 1.00 59.83 4322 CB ALA 756 11.075 38.993 56.870 1.00 60.21 4323 C ALA 756 12.890 39.842 58.372 1.00 61.08 4324 O ALA 756 12.461 39.941 59.531 1.00 61.80 4325 N ALA 757 14.115 39.426 58.072 1.00 62.43 4326 CA ALA 757 15.087 39.099 59.092 1.00 60.57 4327 CB ALA 757 16.415 38.753 58.431 1.00 60.81 4328 C ALA 757 15.211 40.367 59.932 1.00 61.35 4329 O ALA 757 15.146 41.460 59.327 1.00 62.10 4330 OXT ALA 757 15.354 40.253 61.169 1.00 58.48 4331 O HOH 1 62.349 −1.370 59.183 1.00 61.82 4332 O HOH 2 63.098 9.775 56.010 1.00 63.21 4333 O HOH 3 29.467 50.468 47.493 1.00 60.82 4334 O HOH 4 24.799 1.025 51.054 1.00 63.04 4335 O HOH 5 25.120 35.371 29.890 1.00 58.53 4336 O HOH 6 62.603 13.819 69.179 1.00 62.10 4337 O HOH 7 43.394 −0.575 64.086 1.00 61.07 4338 O HOH 8 33.029 27.080 24.812 1.00 63.53 4339 O HOH 9 40.476 0.604 50.517 1.00 62.87 4340 O HOH 10 42.083 33.017 29.431 1.00 59.31 4341 O HOH 11 40.224 −1.905 63.310 1.00 60.38 4342 O HOH 12 29.926 49.219 30.317 1.00 60.19 4343 O HOH 13 63.481 3.211 57.703 1.00 62.93 4344 O HOH 14 45.679 44.833 38.756 1.00 60.97 4345 O HOH 15 21.388 1.839 41.400 1.00 61.41 4346 O HOH 16 47.452 −16.061 63.707 1.00 60.73 4347 O HOH 17 52.653 15.955 63.901 1.00 64.75 4348 O HOH 18 62.913 1.964 67.923 1.00 64.33 4349 O HOH 19 62.507 3.936 69.792 1.00 60.95 4350 O HOH 20 11.730 26.749 44.436 1.00 60.79 4351 O HOH 21 48.735 13.308 64.587 1.00 62.06 4352 O HOH 22 32.377 39.863 58.144 1.00 63.51 4353 O HOH 23 58.924 9.831 70.947 1.00 61.40 4354 O HOH 24 39.278 17.448 64.290 1.00 62.12 4355 O HOH 25 40.573 48.042 36.816 1.00 60.96 4356 O HOH 26 40.494 35.299 48.387 1.00 59.93 4357 O HOH 27 61.454 1.678 61.901 1.00 60.51 4358 O HOH 28 9.075 22.638 42.296 1.00 61.65 4359 O HOH 29 51.369 13.900 63.592 1.00 64.00 4360 O HOH 30 61.184 −0.481 44.937 1.00 61.95 4361 O HOH 31 19.041 16.035 52.737 1.00 60.85 4362 O HOH 32 37.487 3.963 49.092 1.00 60.40 4363 O HOH 33 31.183 34.399 55.395 1.00 61.32 4364 O HOH 34 25.672 33.490 53.795 1.00 61.76 4365 O HOH 35 24.467 27.177 45.107 1.00 62.37 4366 O HOH 36 47.899 30.685 35.691 1.00 60.62 4367 O HOH 37 31.250 45.014 24.427 1.00 63.26 4368 O HOH 38 60.719 −0.340 49.987 1.00 60.94 4369 O HOH 39 48.761 14.305 46.147 1.00 59.45 4370 O HOH 40 52.252 11.824 45.533 1.00 59.86 4371 O HOH 41 40.704 30.604 47.765 1.00 62.04 4372 O HOH 42 34.599 19.541 73.265 1.00 61.69 4373 O HOH 43 44.135 32.951 48.092 1.00 60.11 4374 O HOH 44 16.447 16.136 55.224 1.00 58.77 4375 O HOH 45 37.470 21.079 29.057 1.00 61.47 4376 O HOH 46 14.411 15.785 52.085 1.00 58.97 4377 O HOH 47 27.199 25.588 51.919 1.00 58.58 4378 O HOH 48 32.466 25.097 53.254 1.00 60.88 4379 O HOH 49 17.927 39.612 49.972 1.00 61.48 4380 O HOH 50 17.243 38.022 52.339 1.00 61.61 4381 O HOH 51 65.714 6.374 72.458 1.00 61.45 4382 O HOH 52 25.540 34.686 57.601 1.00 59.81 4383 O HOH 53 22.812 3.452 38.767 1.00 62.42 4384 C1 DEX 1 31.791 3.330 56.615 1.00 59.00 4385 H1 DEX 1 30.892 2.719 56.626 1.00 59.00 4386 C2 DEX 1 32.066 4.057 55.552 1.00 59.00 4387 H2 DEX 1 31.418 4.016 54.717 1.00 59.00 4388 C3 DEX 1 33.314 4.929 55.514 1.00 59.00 4389 C4 DEX 1 34.176 5.061 56.733 1.00 59.00 4390 H4 DEX 1 35.013 5.729 56.720 1.00 59.00 4391 C5 DEX 1 33.915 4.329 57.855 1.00 59.00 4392 C6 DEX 1 34.782 4.456 59.133 1.00 59.00 4393 H61 DEX 1 35.558 5.172 59.015 1.00 59.00 4394 H62 DEX 1 35.262 3.483 59.339 1.00 59.00 4395 C7 DEX 1 33.905 4.834 60.331 1.00 59.00 4396 H71 DEX 1 33.520 5.861 60.202 1.00 59.00 4397 H72 DEX 1 34.515 4.837 61.236 1.00 59.00 4398 C8 DEX 1 32.690 3.903 60.544 1.00 59.00 4399 H8 DEX 1 33.063 2.878 60.787 1.00 59.00 4400 C9 DEX 1 31.759 3.803 59.162 1.00 59.00 4401 C10 DEX 1 32.677 3.304 57.900 1.00 59.00 4402 C11 DEX 1 30.360 2.986 59.327 1.00 59.00 4403 H11 DEX 1 29.743 3.203 58.478 1.00 59.00 4404 C12 DEX 1 29.599 3.415 60.596 1.00 59.00 4405 H121 DEX 1 28.744 2.788 60.729 1.00 59.00 4406 H122 DEX 1 29.221 4.448 60.436 1.00 59.00 4407 C13 DEX 1 30.518 3.414 61.924 1.00 59.00 4408 C14 DEX 1 31.758 4.387 61.726 1.00 59.00 4409 H14 DEX 1 31.359 5.403 61.401 1.00 59.00 4410 C15 DEX 1 32.374 4.589 63.095 1.00 59.00 4411 H151 DEX 1 32.893 5.547 63.111 1.00 59.00 4412 H152 DEX 1 33.119 3.796 63.281 1.00 59.00 4413 C16 DEX 1 31.175 4.486 64.093 1.00 59.00 4414 H16 DEX 1 31.391 3.605 64.743 1.00 59.00 4415 C17 DEX 1 29.863 4.144 63.168 1.00 59.00 4416 C18 DEX 1 30.929 1.834 62.325 1.00 59.00 4417 H181 DEX 1 31.535 1.833 63.241 1.00 59.00 4418 H182 DEX 1 30.050 1.248 62.496 1.00 59.00 4419 H183 DEX 1 31.537 1.374 61.558 1.00 59.00 4420 C19 DEX 1 33.270 1.833 58.015 1.00 59.00 4421 H191 DEX 1 33.916 1.724 58.905 1.00 59.00 4422 H192 DEX 1 32.485 1.095 58.112 1.00 59.00 4423 H193 DEX 1 33.870 1.605 57.134 1.00 59.00 4424 C20 DEX 1 28.759 3.270 63.873 1.00 59.00 4425 C21 DEX 1 27.338 3.348 63.353 1.00 59.00 4426 H211 DEX 1 27.350 3.637 62.283 1.00 59.00 4427 H212 DEX 1 26.827 4.148 63.876 1.00 59.00 4428 C22 DEX 1 31.008 5.693 64.947 1.00 59.00 4429 H221 DEX 1 30.160 5.560 65.619 1.00 59.00 4430 H222 DEX 1 31.912 5.877 65.542 1.00 59.00 4431 H223 DEX 1 30.811 6.588 64.313 1.00 59.00 4432 F1 DEX 1 31.331 5.130 58.833 1.00 59.00 4433 O1 DEX 1 33.617 5.512 54.507 1.00 59.00 4434 O2 DEX 1 30.601 1.580 59.361 1.00 59.00 4435 HO2 DEX 1 29.784 1.163 59.706 1.00 59.00 4436 O3 DEX 1 29.236 5.409 62.711 1.00 59.00 4437 H3 DEX 1 28.816 5.780 63.475 1.00 59.00 4438 O4 DEX 1 29.058 2.511 64.818 1.00 59.00 4439 O5 DEX 1 26.689 2.117 63.492 1.00 59.00 4440 H5 DEX 1 25.816 2.344 63.756 1.00 59.00 4441 C1 DEX 1 21.344 23.582 37.624 1.00 59.00 4442 H1 DEX 1 20.325 23.208 37.634 1.00 59.00 4443 C2 DEX 1 22.105 23.392 38.670 1.00 59.00 4444 H2 DEX 1 21.710 22.910 39.509 1.00 59.00 4445 C3 DEX 1 23.539 23.892 38.687 1.00 59.00 4446 C4 DEX 1 24.137 24.501 37.450 1.00 59.00 4447 H4 DEX 1 25.173 24.791 37.441 1.00 59.00 4448 C5 DEX 1 23.372 24.700 36.346 1.00 59.00 4449 C6 DEX 1 23.965 25.312 35.061 1.00 59.00 4450 H61 DEX 1 24.996 25.542 35.157 1.00 59.00 4451 H62 DEX 1 23.444 26.267 34.853 1.00 59.00 4452 C7 DEX 1 23.752 24.345 33.877 1.00 59.00 4453 H71 DEX 1 24.370 23.444 34.001 1.00 59.00 4454 H72 DEX 1 24.092 24.829 32.956 1.00 59.00 4455 C8 DEX 1 22.275 23.885 33.692 1.00 59.00 4456 H8 DEX 1 21.638 24.764 33.460 1.00 59.00 4457 C9 DEX 1 21.676 23.232 35.081 1.00 59.00 4458 C10 DEX 1 21.819 24.294 36.329 1.00 59.00 4459 C11 DEX 1 20.197 22.585 34.938 1.00 59.00 4460 H11 DEX 1 20.028 21.974 35.784 1.00 59.00 4461 C12 DEX 1 20.107 21.699 33.700 1.00 59.00 4462 H121 DEX 1 19.130 21.365 33.602 1.00 59.00 4463 H122 DEX 1 20.720 20.795 33.859 1.00 59.00 4464 C13 DEX 1 20.600 22.429 32.344 1.00 59.00 4465 C14 DEX 1 22.105 22.863 32.515 1.00 59.00 4466 H14 DEX 1 22.701 21.953 32.834 1.00 59.00 4467 C15 DEX 1 22.602 23.242 31.129 1.00 59.00 4468 H151 DEX 1 23.685 23.110 31.097 1.00 59.00 4469 H152 DEX 1 22.383 24.310 30.934 1.00 59.00 4470 C16 DEX 1 21.806 22.306 30.152 1.00 59.00 4471 H16 DEX 1 21.207 22.984 29.504 1.00 59.00 4472 C17 DEX 1 20.783 21.450 31.097 1.00 59.00 4473 C18 DEX 1 19.540 23.677 31.944 1.00 59.00 4474 H181 DEX 1 19.873 24.157 31.015 1.00 59.00 4475 H182 DEX 1 18.547 23.297 31.792 1.00 59.00 4476 H183 DEX 1 19.525 24.449 32.700 1.00 59.00 4477 C19 DEX 1 20.959 25.638 36.205 1.00 59.00 4478 H191 DEX 1 21.232 26.215 35.303 1.00 59.00 4479 H192 DEX 1 19.899 25.426 36.127 1.00 59.00 4480 H193 DEX 1 21.132 26.270 37.072 1.00 59.00 4481 C20 DEX 1 19.417 21.067 30.421 1.00 59.00 4482 C21 DEX 1 18.443 20.176 31.204 1.00 59.00 4483 H211 DEX 1 17.932 20.800 31.959 1.00 59.00 4484 H212 DEX 1 19.031 19.423 31.779 1.00 59.00 4485 C22 DEX 1 22.671 21.454 29.301 1.00 59.00 4486 H221 DEX 1 22.061 20.835 28.644 1.00 59.00 4487 H222 DEX 1 23.334 22.077 28.688 1.00 59.00 4488 H223 DEX 1 23.300 20.785 29.933 1.00 59.00 4489 F1 DEX 1 22.519 22.128 35.397 1.00 59.00 4490 O1 DEX 1 24.201 23.808 39.692 1.00 59.00 4491 O2 DEX 1 19.179 23.598 34.905 1.00 59.00 4492 HO2 DEX 1 18.367 23.168 34.580 1.00 59.00 4493 O3 DEX 1 21.444 20.210 31.554 1.00 59.00 4494 H3 DEX 1 21.502 19.648 30.802 1.00 59.00 4495 O4 DEX 1 19.127 21.505 29.299 1.00 59.00 4496 O5 DEX 1 17.530 19.572 30.381 1.00 59.00 4497 H5 DEX 1 17.435 18.711 30.744 1.00 59.00

TABLE 5 ATOMIC COORDINATES FOR THE GR/ SRC-1 MODEL USED IN MOLECULAR REPLACEMENT ATOM ATOM TYPE RESIDUE PROTEIN # # X Y Z OCC 1 N GLN 527 −10.228 40.054 15.641 1.00 69.36 2 CA GLN 527 −10.481 38.584 15.329 1.00 66.54 3 C GLN 527 −9.230 37.821 15.751 1.00 66.47 4 O GLN 527 −9.189 37.229 16.832 1.00 66.82 5 CB GLN 527 −10.824 38.264 13.878 1.00 68.47 6 CG GLN 527 −11.131 36.765 13.555 1.00 99.90 7 CD GLN 527 −11.424 36.357 12.106 1.00 99.90 8 OE1 GLN 527 −11.629 35.191 11.807 1.00 99.90 9 NE2 GLN 527 −11.432 37.263 11.161 1.00 99.90 10 N LEU 528 −8.211 37.835 14.896 1.00 63.30 11 CA LEU 528 −6.966 37.146 15.198 1.00 60.85 12 C LEU 528 −5.949 38.070 15.865 1.00 56.94 13 O LEU 528 −5.120 37.612 16.653 1.00 54.60 14 CB LEU 528 −6.361 36.538 13.925 1.00 61.13 15 CG LEU 528 −7.168 35.430 13.235 1.00 66.50 16 CD1 LEU 528 −6.400 34.910 12.020 1.00 60.00 17 CD2 LEU 528 −7.426 34.291 14.214 1.00 59.53 18 N THR 529 −6.012 39.362 15.551 1.00 52.97 19 CA THR 529 −5.083 40.319 16.141 1.00 48.69 20 C THR 529 −5.489 40.584 17.589 1.00 46.25 21 O THR 529 −6.595 41.044 17.853 1.00 41.04 22 CB THR 529 −5.082 41.664 15.381 1.00 52.18 23 OG1 THR 529 −4.666 41.475 14.034 1.00 99.90 24 CG2 THR 529 −4.139 42.758 15.927 1.00 99.90 25 N PRO 530 −4.595 40.292 18.548 1.00 40.66 26 CA PRO 530 −4.883 40.507 19.968 1.00 39.82 27 C PRO 530 −5.301 41.950 20.272 1.00 36.13 28 O PRO 530 −4.811 42.889 19.648 1.00 35.64 29 CB PRO 530 −3.570 40.108 20.640 1.00 34.22 30 CG PRO 530 −3.073 39.021 19.725 1.00 43.36 31 CD PRO 530 −3.240 39.737 18.398 1.00 40.38 32 N THR 531 −6.206 42.135 21.243 1.00 35.29 33 CA THR 531 −6.722 43.444 21.654 1.00 35.12 34 C THR 531 −5.642 44.469 21.993 1.00 30.01 35 O THR 531 −5.687 45.610 21.527 1.00 29.64 36 CB THR 531 −7.584 43.099 22.866 1.00 36.34 37 OG1 THR 531 −8.643 42.227 22.491 1.00 99.90 38 CG2 THR 531 −8.286 44.282 23.567 1.00 99.90 39 N LEU 532 −4.676 44.056 22.805 1.00 29.04 40 CA LEU 532 −3.597 44.958 23.211 1.00 28.23 41 C LEU 532 −2.763 45.434 22.022 1.00 26.62 42 O LEU 532 −2.299 46.580 21.984 1.00 25.82 43 CB LEU 532 −2.702 44.274 24.232 1.00 25.68 44 CG LEU 532 −1.563 45.146 24.757 1.00 34.63 45 CD1 LEU 532 −2.111 46.509 25.197 1.00 30.55 46 CD2 LEU 532 −0.867 44.418 25.902 1.00 30.65 47 N VAL 533 −2.571 44.555 21.045 1.00 27.06 48 CA VAL 533 −1.809 44.925 19.863 1.00 23.18 49 C VAL 533 −2.593 45.921 19.014 1.00 24.05 50 O VAL 533 −2.030 46.890 18.496 1.00 26.77 51 CB VAL 533 −1.442 43.683 19.053 1.00 23.51 52 CG1 VAL 533 −0.483 42.716 19.788 1.00 99.90 53 CG2 VAL 533 −0.787 43.933 17.666 1.00 99.90 54 N SER 534 −3.900 45.708 18.871 1.00 25.92 55 CA SER 534 −4.703 46.659 18.103 1.00 27.71 56 C SER 534 −4.657 48.017 18.811 1.00 22.00 57 O SER 534 −4.612 49.063 18.165 1.00 26.26 58 CB SER 534 −6.156 46.179 17.998 1.00 31.49 59 OG SER 534 −6.853 46.235 19.247 1.00 99.90 60 N LEU 535 −4.662 48.000 20.140 1.00 26.88 61 CA LEU 535 −4.620 49.258 20.894 1.00 25.43 62 C LEU 535 −3.296 49.974 20.628 1.00 27.05 63 O LEU 535 −3.273 51.177 20.377 1.00 26.07 64 CB LEU 535 −4.802 48.981 22.385 1.00 26.35 65 CG LEU 535 −4.863 50.186 23.336 1.00 35.60 66 CD1 LEU 535 −5.553 49.756 24.633 1.00 36.71 67 CD2 LEU 535 −3.464 50.735 23.618 1.00 30.46 68 N LEU 536 −2.197 49.230 20.652 1.00 25.73 69 CA LEU 536 −0.883 49.817 20.384 1.00 23.64 70 C LEU 536 −0.843 50.404 18.977 1.00 27.62 71 O LEU 536 −0.242 51.450 18.756 1.00 22.81 72 CB LEU 536 0.221 48.764 20.527 1.00 24.64 73 CG LEU 536 0.433 48.131 21.906 1.00 25.70 74 CD1 LEU 536 1.559 47.084 21.835 1.00 21.63 75 CD2 LEU 536 0.782 49.226 22.923 1.00 20.83 76 N GLU 537 −1.455 49.717 18.013 1.00 24.62 77 CA GLU 537 −1.488 50.230 16.646 1.00 27.60 78 C GLU 537 −2.257 51.555 16.668 1.00 27.94 79 O GLU 537 −1.850 52.543 16.060 1.00 25.86 80 CB GLU 537 −2.207 49.232 15.730 1.00 27.45 81 CG GLU 537 −2.284 49.639 14.284 1.00 39.52 82 CD GLU 537 −3.073 48.750 13.320 1.00 99.90 83 OE1 GLU 537 −3.217 49.017 12.134 1.00 99.90 84 OE2 GLU 537 −3.596 47.637 13.905 1.00 99.90 85 N VAL 538 −3.358 51.575 17.406 1.00 25.24 86 CA VAL 538 −4.180 52.769 17.476 1.00 31.97 87 C VAL 538 −3.512 53.961 18.152 1.00 29.88 88 O VAL 538 −3.776 55.107 17.786 1.00 28.14 89 CB VAL 538 −5.505 52.468 18.192 1.00 38.05 90 CG1 VAL 538 −6.415 51.472 17.434 1.00 99.90 91 CG2 VAL 538 −6.410 53.691 18.509 1.00 99.90 92 N ILE 539 −2.649 53.719 19.132 1.00 25.23 93 CA ILE 539 −2.029 54.861 19.808 1.00 26.22 94 C ILE 539 −0.676 55.270 19.251 1.00 23.06 95 O ILE 539 −0.047 56.183 19.773 1.00 24.41 96 CB ILE 539 −1.882 54.630 21.329 1.00 22.83 97 CG1 ILE 539 −0.980 53.420 21.599 1.00 22.20 98 CG2 ILE 539 −3.272 54.416 21.956 1.00 28.20 99 CD1 ILE 539 −0.532 53.297 23.062 1.00 22.62 100 N GLU 540 −0.226 54.598 18.192 1.00 26.89 101 CA GLU 540 1.057 54.934 17.586 1.00 21.93 102 C GLU 540 0.876 56.354 17.033 1.00 28.96 103 O GLU 540 −0.099 56.649 16.351 1.00 29.21 104 CB GLU 540 1.375 53.934 16.466 1.00 34.17 105 CG GLU 540 2.763 54.039 15.856 1.00 34.86 106 CD GLU 540 3.897 53.587 16.769 1.00 45.46 107 OE1 GLU 540 3.672 53.281 17.966 1.00 31.19 108 OE2 GLU 540 5.046 53.539 16.270 1.00 49.30 109 N PRO 541 1.795 57.264 17.354 1.00 32.33 110 CA PRO 541 1.659 58.635 16.856 1.00 34.70 111 C PRO 541 1.667 58.767 15.331 1.00 30.39 112 O PRO 541 2.212 57.925 14.636 1.00 27.63 113 CB PRO 541 2.849 59.338 17.508 1.00 38.27 114 CG PRO 541 3.883 58.205 17.590 1.00 40.07 115 CD PRO 541 2.996 57.145 18.198 1.00 34.72 116 N GLU 542 1.059 59.843 14.830 1.00 38.27 117 CA GLU 542 1.016 60.116 13.393 1.00 35.46 118 C GLU 542 2.448 60.549 13.036 1.00 35.96 119 O GLU 542 3.146 61.098 13.878 1.00 30.43 120 CB GLU 542 0.019 61.240 13.114 1.00 44.25 121 CG GLU 542 0.362 62.659 13.675 1.00 99.90 122 CD GLU 542 −0.666 63.779 13.498 1.00 99.90 123 OE1 GLU 542 −0.499 64.911 13.930 1.00 99.90 124 OE2 GLU 542 −1.781 63.396 12.815 1.00 99.90 125 N VAL 543 2.894 60.309 11.807 1.00 32.80 126 CA VAL 543 4.265 60.673 11.442 1.00 34.66 127 C VAL 543 4.614 62.131 11.776 1.00 28.44 128 O VAL 543 3.816 63.045 11.605 1.00 30.11 129 CB VAL 543 4.552 60.403 9.937 1.00 41.68 130 CG1 VAL 543 3.962 61.509 9.080 1.00 38.06 131 CG2 VAL 543 6.058 60.258 9.715 1.00 45.80 132 N LEU 544 5.823 62.324 12.280 1.00 30.17 133 CA LEU 544 6.298 63.640 12.668 1.00 26.23 134 C LEU 544 7.221 64.217 11.601 1.00 28.40 135 O LEU 544 8.113 63.526 11.118 1.00 22.17 136 CB LEU 544 7.089 63.668 14.010 1.00 28.58 137 CG LEU 544 6.289 64.066 15.279 1.00 99.90 138 CD1 LEU 544 5.742 65.511 15.198 1.00 99.90 139 CD2 LEU 544 5.145 63.088 15.608 1.00 99.90 140 N TYR 545 7.000 65.477 11.239 1.00 23.87 141 CA TYR 545 7.839 66.165 10.260 1.00 27.94 142 C TYR 545 8.960 66.895 10.979 1.00 28.04 143 O TYR 545 8.794 67.338 12.116 1.00 24.24 144 CB TYR 545 7.010 67.159 9.460 1.00 27.40 145 CG TYR 545 6.083 66.476 8.487 1.00 34.60 146 CD1 TYR 545 4.825 66.038 8.889 1.00 37.81 147 CD2 TYR 545 6.489 66.207 7.181 1.00 38.29 148 CE1 TYR 545 3.992 65.348 8.016 1.00 47.26 149 CE2 TYR 545 5.661 65.516 6.295 1.00 39.38 150 CZ TYR 545 4.414 65.090 6.724 1.00 41.71 151 OH TYR 545 3.599 64.389 5.864 1.00 52.51 152 N ALA 546 10.110 67.022 10.328 1.00 23.60 153 CA ALA 546 11.213 67.720 10.964 1.00 26.37 154 C ALA 546 11.100 69.231 10.756 1.00 29.47 155 O ALA 546 11.688 70.011 11.510 1.00 28.14 156 CB ALA 546 12.542 67.231 10.418 1.00 27.79 157 N GLY 547 10.332 69.635 9.749 1.00 29.99 158 CA GLY 547 10.213 71.051 9.439 1.00 32.21 159 C GLY 547 11.541 71.501 8.836 1.00 39.13 160 O GLY 547 11.964 72.645 8.992 1.00 40.76 161 N TYR 548 12.206 70.581 8.140 1.00 38.38 162 CA TYR 548 13.505 70.850 7.528 1.00 46.41 163 C TYR 548 13.429 71.638 6.208 1.00 47.68 164 O TYR 548 12.536 71.420 5.391 1.00 49.96 165 CB TYR 548 14.242 69.521 7.333 1.00 42.73 166 CG TYR 548 15.579 69.661 6.681 1.00 48.58 167 CD1 TYR 548 16.740 69.612 7.459 1.00 99.90 168 CD2 TYR 548 15.683 69.849 5.299 1.00 99.90 169 CE1 TYR 548 17.990 69.755 6.864 1.00 99.90 170 CE2 TYR 548 16.935 69.992 4.706 1.00 99.90 171 CZ TYR 548 18.085 69.945 5.488 1.00 99.90 172 OH TYR 548 19.311 70.089 4.902 1.00 99.90 173 N ASP 549 14.389 72.543 6.016 1.00 51.90 174 CA ASP 549 14.465 73.400 4.832 1.00 52.61 175 C ASP 549 14.420 72.658 3.499 1.00 54.82 176 O ASP 549 13.434 72.755 2.768 1.00 57.82 177 CB ASP 549 15.727 74.257 4.903 1.00 52.84 178 CG ASP 549 15.881 75.347 3.832 1.00 99.90 179 OD1 ASP 549 16.948 75.607 3.295 1.00 99.90 180 OD2 ASP 549 14.700 75.968 3.534 1.00 99.90 181 N SER 550 15.499 71.940 3.190 1.00 55.70 182 CA SER 550 15.638 71.176 1.951 1.00 56.60 183 C SER 550 16.129 72.063 0.803 1.00 60.14 184 O SER 550 17.143 71.764 0.160 1.00 61.18 185 CB SER 550 14.308 70.509 1.579 1.00 57.02 186 OG SER 550 13.309 71.449 1.168 1.00 99.90 187 N SER 551 15.414 73.153 0.549 1.00 59.68 188 CA SER 551 15.776 74.077 −0.525 1.00 60.50 189 C SER 551 17.217 74.596 −0.418 1.00 61.78 190 O SER 551 17.813 74.999 −1.421 1.00 61.98 191 CB SER 551 14.797 75.251 −0.544 1.00 57.03 192 OG SER 551 14.942 76.115 0.588 1.00 99.90 193 N VAL 552 17.779 74.588 0.789 1.00 62.40 194 CA VAL 552 19.146 75.067 0.984 1.00 64.42 195 C VAL 552 20.127 73.906 1.141 1.00 66.61 196 O VAL 552 19.730 72.783 1.477 1.00 64.83 197 CB VAL 552 19.212 75.972 2.210 1.00 60.35 198 CG1 VAL 552 18.401 77.282 2.067 1.00 99.90 199 CG2 VAL 552 20.631 76.416 2.664 1.00 99.90 200 N PRO 553 21.421 74.158 0.871 1.00 67.95 201 CA PRO 553 22.478 73.146 0.982 1.00 69.09 202 C PRO 553 22.696 72.762 2.450 1.00 68.98 203 O PRO 553 23.139 73.581 3.258 1.00 70.54 204 CB PRO 553 23.694 73.862 0.379 1.00 71.22 205 CG PRO 553 23.056 74.901 −0.556 1.00 69.09 206 CD PRO 553 22.000 75.422 0.389 1.00 68.58 207 N ASP 554 22.391 71.512 2.783 1.00 68.95 208 CA ASP 554 22.527 71.018 4.150 1.00 68.41 209 C ASP 554 23.968 70.915 4.646 1.00 65.11 210 O ASP 554 24.764 70.158 4.094 1.00 67.29 211 CB ASP 554 21.883 69.631 4.276 1.00 72.12 212 CG ASP 554 20.413 69.618 3.875 1.00 74.27 213 OD1 ASP 554 19.882 70.676 3.471 1.00 77.63 214 OD2 ASP 554 19.791 68.538 3.964 1.00 75.63 215 N SER 555 24.301 71.673 5.689 1.00 61.36 216 CA SER 555 25.640 71.597 6.262 1.00 54.04 217 C SER 555 25.561 70.578 7.393 1.00 53.38 218 O SER 555 24.471 70.198 7.818 1.00 44.49 219 CB SER 555 26.118 72.959 6.830 1.00 56.37 220 OG SER 555 25.403 73.353 8.005 1.00 99.90 221 N THR 556 26.710 70.123 7.873 1.00 47.04 222 CA THR 556 26.725 69.148 8.945 1.00 48.03 223 C THR 556 26.006 69.688 10.180 1.00 44.05 224 O THR 556 25.178 68.999 10.773 1.00 41.23 225 CB THR 556 28.189 68.850 9.368 1.00 50.15 226 OG1 THR 556 28.903 68.203 8.319 1.00 99.90 227 CG2 THR 556 28.263 68.016 10.654 1.00 99.90 228 N TRP 557 26.306 70.925 10.556 1.00 37.98 229 CA TRP 557 25.673 71.524 11.726 1.00 39.84 230 C TRP 557 24.187 71.832 11.510 1.00 37.46 231 O TRP 557 23.393 71.743 12.449 1.00 35.48 232 CB TRP 557 26.399 72.802 12.203 1.00 40.58 233 CG TRP 557 26.434 73.958 11.232 1.00 99.90 234 CD1 TRP 557 27.544 74.313 10.390 1.00 99.90 235 CD2 TRP 557 25.452 74.961 11.022 1.00 99.90 236 NE1 TRP 557 27.245 75.473 9.684 1.00 99.90 237 CE2 TRP 557 25.973 75.857 10.063 1.00 99.90 238 CE3 TRP 557 24.158 75.198 11.599 1.00 99.90 239 CZ2 TRP 557 25.272 77.008 9.578 1.00 99.90 240 CZ3 TRP 557 23.408 76.344 11.133 1.00 99.90 241 CH2 TRP 557 23.957 77.238 10.130 1.00 99.90 242 N ARG 558 23.800 72.201 10.291 1.00 36.47 243 CA ARG 558 22.391 72.504 10.047 1.00 34.65 244 C ARG 558 21.619 71.191 10.107 1.00 31.60 245 O ARG 558 20.506 71.126 10.623 1.00 28.24 246 CB ARG 558 22.184 73.186 8.679 1.00 35.58 247 CG ARG 558 20.779 73.811 8.448 1.00 99.90 248 CD ARG 558 20.649 74.442 7.052 1.00 99.90 249 NE ARG 558 19.294 75.048 6.898 1.00 99.90 250 CZ ARG 558 18.852 75.678 5.814 1.00 99.90 251 NH1 ARG 558 17.650 76.161 5.831 1.00 99.90 252 NH2 ARG 558 19.562 75.839 4.733 1.00 99.90 253 N ILE 559 22.229 70.139 9.588 1.00 27.90 254 CA ILE 559 21.613 68.820 9.602 1.00 29.29 255 C ILE 559 21.345 68.364 11.043 1.00 28.57 256 O ILE 559 20.232 67.953 11.369 1.00 25.88 257 CB ILE 559 22.406 67.656 8.915 1.00 27.95 258 CG2 ILE 559 21.832 66.259 9.270 1.00 99.90 259 CG1 ILE 559 22.415 67.806 7.377 1.00 99.90 260 CD1 ILE 559 23.458 66.951 6.630 1.00 99.90 261 N MET 560 22.364 68.445 11.894 1.00 25.56 262 CA MET 560 22.212 68.046 13.295 1.00 24.24 263 C MET 560 21.180 68.886 13.992 1.00 22.49 264 O MET 560 20.386 68.365 14.764 1.00 21.35 265 CB MET 560 23.550 68.151 14.056 1.00 24.95 266 CG MET 560 24.525 67.005 13.723 1.00 99.90 267 SD MET 560 23.920 65.411 14.376 1.00 99.90 268 CE MET 560 24.920 64.276 13.373 1.00 99.90 269 N THR 561 21.176 70.188 13.712 1.00 21.24 270 CA THR 561 20.191 71.086 14.293 1.00 24.54 271 C THR 561 18.791 70.654 13.870 1.00 24.54 272 O THR 561 17.868 70.652 14.680 1.00 21.07 273 CB THR 561 20.428 72.551 13.849 1.00 24.90 274 OG1 THR 561 21.608 73.099 14.433 1.00 26.56 275 CG2 THR 561 19.251 73.435 14.239 1.00 23.35 276 N THR 562 18.623 70.304 12.598 1.00 19.11 277 CA THR 562 17.325 69.852 12.125 1.00 21.51 278 C THR 562 16.950 68.510 12.763 1.00 19.84 279 O THR 562 15.765 68.271 13.043 1.00 21.66 280 CB THR 562 17.209 69.868 10.626 1.00 24.02 281 OG1 THR 562 18.182 69.009 10.045 1.00 99.90 282 CG2 THR 562 17.280 71.338 10.099 1.00 99.90 283 N LEU 563 17.928 67.625 12.974 1.00 18.47 284 CA LEU 563 17.608 66.344 13.600 1.00 20.90 285 C LEU 563 17.233 66.563 15.064 1.00 20.84 286 O LEU 563 16.408 65.823 15.626 1.00 20.00 287 CB LEU 563 18.779 65.376 13.501 1.00 17.55 288 CG LEU 563 19.050 64.828 12.100 1.00 19.20 289 CD1 LEU 563 20.349 64.062 12.128 1.00 20.15 290 CD2 LEU 563 17.907 63.924 11.653 1.00 19.08 291 N ASN 564 17.833 67.569 15.695 1.00 17.81 292 CA ASN 564 17.467 67.856 17.098 1.00 19.99 293 C ASN 564 16.053 68.424 17.186 1.00 18.99 294 O ASN 564 15.333 68.155 18.142 1.00 20.08 295 CB ASN 564 18.437 68.841 17.766 1.00 22.67 296 CG ASN 564 19.770 68.211 18.120 1.00 27.38 297 OD1 ASN 564 19.868 66.996 18.368 1.00 24.69 298 ND2 ASN 564 20.855 69.103 18.180 1.00 23.33 299 N MET 565 15.665 69.235 16.207 1.00 18.44 300 CA MET 565 14.315 69.814 16.170 1.00 21.61 301 C MET 565 13.323 68.659 16.001 1.00 23.93 302 O MET 565 12.274 68.623 16.642 1.00 18.25 303 CB MET 565 14.184 70.806 15.004 1.00 22.65 304 CG MET 565 12.747 71.298 14.744 1.00 26.41 305 SD MET 565 12.649 72.592 13.455 1.00 99.90 306 CE MET 565 13.095 74.057 14.453 1.00 99.90 307 N LEU 566 13.671 67.699 15.143 1.00 19.58 308 CA LEU 566 12.817 66.527 14.951 1.00 17.13 309 C LEU 566 12.746 65.757 16.277 1.00 16.29 310 O LEU 566 11.671 65.324 16.696 1.00 19.55 311 CB LEU 566 13.387 65.627 13.840 1.00 17.00 312 CG LEU 566 12.612 64.333 13.581 1.00 19.10 313 CD1 LEU 566 11.169 64.658 13.155 1.00 18.65 314 CD2 LEU 566 13.358 63.527 12.488 1.00 17.08 315 N GLY 567 13.893 65.600 16.928 1.00 16.83 316 CA GLY 567 13.964 64.895 18.202 1.00 17.42 317 C GLY 567 13.076 65.551 19.250 1.00 24.76 318 O GLY 567 12.414 64.868 20.039 1.00 19.56 319 N GLY 568 13.060 66.880 19.270 1.00 20.84 320 CA GLY 568 12.208 67.618 20.227 1.00 22.88 321 C GLY 568 10.745 67.300 19.943 1.00 23.92 322 O GLY 568 9.941 67.105 20.861 1.00 23.22 323 N ARG 569 10.383 67.247 18.663 1.00 17.75 324 CA ARG 569 9.003 66.943 18.297 1.00 19.86 325 C ARG 569 8.645 65.488 18.579 1.00 18.81 326 O ARG 569 7.487 65.185 18.891 1.00 20.56 327 CB ARG 569 8.759 67.252 16.822 1.00 18.63 328 CG ARG 569 8.968 68.720 16.487 1.00 24.16 329 CD ARG 569 8.809 68.967 15.007 1.00 28.88 330 NE ARG 569 9.078 70.364 14.697 1.00 27.71 331 CZ ARG 569 8.799 70.947 13.543 1.00 32.19 332 NH1 ARG 569 8.220 70.275 12.501 1.00 28.19 333 NH2 ARG 569 9.059 72.280 13.407 1.00 35.89 334 N GLN 570 9.610 64.584 18.434 1.00 19.77 335 CA GLN 570 9.347 63.185 18.733 1.00 19.30 336 C GLN 570 9.290 62.930 20.235 1.00 21.49 337 O GLN 570 8.579 62.041 20.686 1.00 21.43 338 CB GLN 570 10.402 62.278 18.090 1.00 19.47 339 CG GLN 570 10.243 62.249 16.570 1.00 22.41 340 CD GLN 570 11.136 61.224 15.896 1.00 30.53 341 OE1 GLN 570 11.158 61.113 14.660 1.00 32.93 342 NE2 GLN 570 11.855 60.320 16.694 1.00 27.09 343 N VAL 571 10.026 63.719 21.013 1.00 21.82 344 CA VAL 571 10.012 63.557 22.464 1.00 22.79 345 C VAL 571 8.605 63.860 22.974 1.00 21.40 346 O VAL 571 8.070 63.124 23.814 1.00 23.41 347 CB VAL 571 11.050 64.461 23.230 1.00 19.53 348 CG1 VAL 571 12.095 63.635 24.008 1.00 99.90 349 CG2 VAL 571 10.473 65.473 24.249 1.00 99.90 350 N ILE 572 8.003 64.934 22.463 1.00 18.00 351 CA ILE 572 6.645 65.281 22.849 1.00 19.91 352 C ILE 572 5.737 64.105 22.494 1.00 24.23 353 O ILE 572 4.905 63.659 23.291 1.00 19.07 354 CB ILE 572 6.158 66.513 22.085 1.00 21.64 355 CG2 ILE 572 4.737 66.978 22.530 1.00 99.90 356 CG1 ILE 572 7.116 67.745 22.156 1.00 99.90 357 CD1 ILE 572 6.829 68.881 21.152 1.00 99.90 358 N ALA 573 5.914 63.605 21.276 1.00 21.94 359 CA ALA 573 5.113 62.497 20.783 1.00 21.38 360 C ALA 573 5.250 61.280 21.696 1.00 20.10 361 O ALA 573 4.249 60.628 22.014 1.00 22.32 362 CB ALA 573 5.529 62.155 19.344 1.00 24.08 363 N ALA 574 6.470 60.965 22.106 1.00 18.72 364 CA ALA 574 6.727 59.847 23.015 1.00 20.27 365 C ALA 574 6.016 59.998 24.355 1.00 18.31 366 O ALA 574 5.435 59.040 24.866 1.00 19.16 367 CB ALA 574 8.233 59.670 23.290 1.00 17.15 368 N VAL 575 6.053 61.190 24.932 1.00 17.43 369 CA VAL 575 5.395 61.372 26.212 1.00 21.44 370 C VAL 575 3.881 61.250 26.044 1.00 19.86 371 O VAL 575 3.229 60.652 26.888 1.00 21.47 372 CB VAL 575 5.767 62.724 26.853 1.00 20.22 373 CG1 VAL 575 5.044 62.890 28.196 1.00 21.24 374 CG2 VAL 575 7.267 62.791 27.055 1.00 19.32 375 N LYS 576 3.321 61.798 24.964 1.00 17.73 376 CA LYS 576 1.887 61.669 24.724 1.00 22.58 377 C LYS 576 1.511 60.201 24.534 1.00 23.23 378 O LYS 576 0.505 59.724 25.073 1.00 20.64 379 CB LYS 576 1.449 62.508 23.520 1.00 23.07 380 CG LYS 576 1.382 64.007 23.862 1.00 25.92 381 CD LYS 576 0.670 64.861 22.804 1.00 37.08 382 CE LYS 576 1.481 65.021 21.529 1.00 48.50 383 NZ LYS 576 0.886 65.984 20.514 1.00 49.18 384 N TRP 577 2.324 59.485 23.767 1.00 18.73 385 CA TRP 577 2.103 58.062 23.544 1.00 21.37 386 C TRP 577 2.085 57.301 24.865 1.00 22.20 387 O TRP 577 1.214 56.463 25.089 1.00 23.93 388 CB TRP 577 3.212 57.516 22.647 1.00 21.47 389 CG TRP 577 3.324 56.016 22.560 1.00 17.78 390 CD1 TRP 577 2.491 55.147 21.892 1.00 20.71 391 CD2 TRP 577 4.384 55.226 23.086 1.00 17.23 392 NE1 TRP 577 2.986 53.867 21.972 1.00 19.88 393 CE2 TRP 577 4.149 53.887 22.699 1.00 19.41 394 CE3 TRP 577 5.525 55.520 23.852 1.00 19.83 395 CZ2 TRP 577 5.018 52.839 23.050 1.00 18.15 396 CZ3 TRP 577 6.395 54.472 24.201 1.00 20.23 397 CH2 TRP 577 6.129 53.149 23.796 1.00 22.27 398 N ALA 578 3.026 57.612 25.754 1.00 20.68 399 CA ALA 578 3.119 56.904 27.029 1.00 22.57 400 C ALA 578 1.893 57.109 27.916 1.00 20.83 401 O ALA 578 1.580 56.253 28.722 1.00 22.59 402 CB ALA 578 4.383 57.328 27.800 1.00 22.82 403 N LYS 579 1.209 58.242 27.768 1.00 20.76 404 CA LYS 579 0.034 58.523 28.591 1.00 25.82 405 C LYS 579 −1.139 57.644 28.160 1.00 26.99 406 O LYS 579 −2.099 57.463 28.917 1.00 24.98 407 CB LYS 579 −0.343 60.011 28.504 1.00 27.35 408 CG LYS 579 0.830 60.916 28.818 1.00 34.69 409 CD LYS 579 0.432 62.175 29.587 1.00 44.84 410 CE LYS 579 −0.567 63.030 28.838 1.00 49.64 411 NZ LYS 579 −1.041 64.247 29.618 1.00 49.55 412 N ALA 580 −1.063 57.101 26.947 1.00 23.17 413 CA ALA 580 −2.110 56.201 26.454 1.00 23.40 414 C ALA 580 −1.690 54.735 26.489 1.00 24.42 415 O ALA 580 −2.505 53.841 26.216 1.00 21.97 416 CB ALA 580 −2.504 56.563 25.016 1.00 24.11 417 N ILE 581 −0.427 54.480 26.834 1.00 19.77 418 CA ILE 581 0.106 53.112 26.852 1.00 21.02 419 C ILE 581 −0.434 52.326 28.032 1.00 21.28 420 O ILE 581 −0.175 52.679 29.172 1.00 22.53 421 CB ILE 581 1.639 53.156 26.928 1.00 23.10 422 CG2 ILE 581 2.289 51.739 26.862 1.00 99.90 423 CG1 ILE 581 2.320 54.053 25.845 1.00 99.90 424 CD1 ILE 581 3.809 54.379 26.080 1.00 99.90 425 N PRO 582 −1.142 51.218 27.773 1.00 22.85 426 CA PRO 582 −1.688 50.455 28.903 1.00 24.25 427 C PRO 582 −0.693 50.121 30.008 1.00 25.32 428 O PRO 582 0.380 49.563 29.756 1.00 25.05 429 CB PRO 582 −2.273 49.215 28.221 1.00 24.36 430 CG PRO 582 −2.742 49.779 26.893 1.00 23.83 431 CD PRO 582 −1.474 50.547 26.502 1.00 20.46 432 N GLY 583 −1.064 50.493 31.233 1.00 25.15 433 CA GLY 583 −0.240 50.226 32.397 1.00 25.65 434 C GLY 583 0.794 51.272 32.770 1.00 23.09 435 O GLY 583 1.172 51.397 33.932 1.00 25.86 436 N PHE 584 1.247 52.055 31.804 1.00 22.74 437 CA PHE 584 2.289 53.021 32.116 1.00 23.63 438 C PHE 584 1.874 54.103 33.106 1.00 22.42 439 O PHE 584 2.605 54.395 34.041 1.00 21.78 440 CB PHE 584 2.800 53.696 30.832 1.00 21.38 441 CG PHE 584 4.125 54.391 31.005 1.00 20.80 442 CD1 PHE 584 5.284 53.639 31.225 1.00 22.81 443 CD2 PHE 584 4.221 55.780 30.956 1.00 24.10 444 CE1 PHE 584 6.512 54.254 31.389 1.00 24.39 445 CE2 PHE 584 5.458 56.409 31.121 1.00 19.38 446 CZ PHE 584 6.597 55.644 31.336 1.00 23.48 447 N ARG 585 0.696 54.688 32.899 1.00 22.15 448 CA ARG 585 0.230 55.780 33.752 1.00 25.70 449 C ARG 585 0.022 55.358 35.192 1.00 24.37 450 O ARG 585 −0.142 56.197 36.080 1.00 24.34 451 CB ARG 585 −1.081 56.353 33.225 1.00 23.04 452 CG ARG 585 −2.193 55.320 33.145 1.00 24.68 453 CD ARG 585 −3.541 56.001 32.956 1.00 25.40 454 NE ARG 585 −4.603 55.003 32.931 1.00 24.48 455 CZ ARG 585 −5.894 55.292 32.940 1.00 20.47 456 NH1 ARG 585 −6.370 56.573 33.000 1.00 23.59 457 NH2 ARG 585 −6.788 54.265 32.887 1.00 26.38 458 N ASN 586 0.040 54.056 35.420 1.00 27.20 459 CA ASN 586 −0.174 53.518 36.748 1.00 23.55 460 C ASN 586 1.103 53.371 37.564 1.00 26.53 461 O ASN 586 1.037 53.106 38.766 1.00 27.16 462 CB ASN 586 −0.930 52.210 36.617 1.00 32.06 463 CG ASN 586 −2.263 52.399 35.915 1.00 33.85 464 OD1 ASN 586 −2.792 51.484 35.293 1.00 37.94 465 ND2 ASN 586 −3.004 53.573 36.197 1.00 28.27 466 N LEU 587 2.256 53.542 36.920 1.00 22.63 467 CA LEU 587 3.532 53.511 37.620 1.00 22.51 468 C LEU 587 3.617 54.863 38.294 1.00 19.73 469 O LEU 587 2.941 55.801 37.907 1.00 23.16 470 CB LEU 587 4.713 53.393 36.649 1.00 21.95 471 CG LEU 587 4.686 52.151 35.762 1.00 20.73 472 CD1 LEU 587 5.770 52.276 34.661 1.00 23.47 473 CD2 LEU 587 4.890 50.905 36.624 1.00 22.85 474 N HIS 588 4.454 54.948 39.308 1.00 21.02 475 CA HIS 588 4.661 56.192 40.037 1.00 25.86 476 C HIS 588 5.125 57.217 39.005 1.00 26.17 477 O HIS 588 5.834 56.860 38.072 1.00 23.09 478 CB HIS 588 5.727 55.921 41.100 1.00 28.77 479 CG HIS 588 5.930 57.038 42.066 1.00 36.70 480 ND1 HIS 588 6.543 58.220 41.718 1.00 34.14 481 CD2 HIS 588 5.612 57.149 43.377 1.00 38.95 482 CE1 HIS 588 6.598 59.012 42.775 1.00 39.45 483 NE2 HIS 588 6.039 58.385 43.794 1.00 39.37 484 N LEU 589 4.717 58.477 39.156 1.00 20.73 485 CA LEU 589 5.113 59.520 38.215 1.00 27.73 486 C LEU 589 6.627 59.635 38.061 1.00 27.07 487 O LEU 589 7.137 59.841 36.948 1.00 24.14 488 CB LEU 589 4.534 60.892 38.625 1.00 26.09 489 CG LEU 589 2.993 61.022 38.767 1.00 99.90 490 CD1 LEU 589 2.612 62.479 39.068 1.00 99.90 491 CD2 LEU 589 2.238 60.537 37.518 1.00 99.90 492 N ASP 590 7.362 59.511 39.164 1.00 24.97 493 CA ASP 590 8.811 59.597 39.074 1.00 27.70 494 C ASP 590 9.369 58.468 38.212 1.00 25.79 495 O ASP 590 10.365 58.653 37.515 1.00 26.38 496 CB ASP 590 9.479 59.536 40.452 1.00 33.81 497 CG ASP 590 9.143 60.731 41.321 1.00 46.44 498 OD1 ASP 590 8.821 61.801 40.763 1.00 51.31 499 OD2 ASP 590 9.238 60.609 42.566 1.00 50.96 500 N ASP 591 8.744 57.299 38.279 1.00 23.70 501 CA ASP 591 9.199 56.177 37.478 1.00 22.43 502 C ASP 591 8.872 56.433 36.012 1.00 19.90 503 O ASP 591 9.691 56.138 35.140 1.00 22.60 504 CB ASP 591 8.551 54.870 37.911 1.00 21.92 505 CG ASP 591 8.827 54.538 39.355 1.00 33.42 506 OD1 ASP 591 9.882 54.978 39.884 1.00 34.56 507 OD2 ASP 591 7.996 53.817 39.949 1.00 39.54 508 N GLN 592 7.698 57.001 35.742 1.00 19.31 509 CA GLN 592 7.307 57.263 34.357 1.00 17.71 510 C GLN 592 8.321 58.215 33.762 1.00 23.99 511 O GLN 592 8.813 57.992 32.663 1.00 19.91 512 CB GLN 592 5.924 57.901 34.270 1.00 19.37 513 CG GLN 592 4.823 57.083 34.901 1.00 22.18 514 CD GLN 592 3.473 57.742 34.779 1.00 22.76 515 OE1 GLN 592 2.619 57.600 35.656 1.00 25.01 516 NE2 GLN 592 3.183 58.456 33.594 1.00 18.79 517 N MET 593 8.623 59.289 34.485 1.00 21.08 518 CA MET 593 9.602 60.249 33.999 1.00 21.96 519 C MET 593 10.973 59.607 33.797 1.00 24.64 520 O MET 593 11.599 59.811 32.755 1.00 23.28 521 CB MET 593 9.727 61.448 34.968 1.00 25.55 522 CG MET 593 8.454 62.300 35.153 1.00 99.90 523 SD MET 593 8.851 63.799 36.068 1.00 99.90 524 CE MET 593 7.176 64.333 36.445 1.00 99.90 525 N THR 594 11.439 58.840 34.785 1.00 19.75 526 CA THR 594 12.733 58.166 34.705 1.00 20.18 527 C THR 594 12.812 57.212 33.499 1.00 19.01 528 O THR 594 13.815 57.184 32.799 1.00 18.23 529 CB THR 594 13.014 57.344 35.986 1.00 24.15 530 OG1 THR 594 13.099 58.173 37.142 1.00 26.23 531 CG2 THR 594 14.347 56.633 35.879 1.00 23.53 532 N LEU 595 11.761 56.428 33.256 1.00 17.46 533 CA LEU 595 11.778 55.502 32.116 1.00 19.07 534 C LEU 595 11.867 56.218 30.760 1.00 17.18 535 O LEU 595 12.533 55.729 29.840 1.00 17.28 536 CB LEU 595 10.544 54.590 32.139 1.00 18.92 537 CG LEU 595 10.566 53.657 33.371 1.00 22.74 538 CD1 LEU 595 9.226 52.941 33.555 1.00 22.99 539 CD2 LEU 595 11.672 52.663 33.188 1.00 20.48 540 N LEU 596 11.172 57.343 30.631 1.00 16.29 541 CA LEU 596 11.231 58.127 29.386 1.00 23.76 542 C LEU 596 12.630 58.735 29.234 1.00 22.00 543 O LEU 596 13.213 58.713 28.148 1.00 17.05 544 CB LEU 596 10.153 59.246 29.361 1.00 18.60 545 CG LEU 596 8.665 58.830 29.513 1.00 99.90 546 CD1 LEU 596 7.756 60.057 29.351 1.00 99.90 547 CD2 LEU 596 8.247 57.740 28.512 1.00 99.90 548 N GLN 597 13.180 59.275 30.318 1.00 21.43 549 CA GLN 597 14.516 59.863 30.216 1.00 23.26 550 C GLN 597 15.596 58.825 29.922 1.00 22.82 551 O GLN 597 16.616 59.155 29.340 1.00 22.26 552 CB GLN 597 14.856 60.678 31.478 1.00 21.04 553 CG GLN 597 13.846 61.816 31.674 1.00 26.41 554 CD GLN 597 14.176 62.744 32.833 1.00 34.88 555 OE1 GLN 597 14.610 62.307 33.897 1.00 28.80 556 NE2 GLN 597 13.918 64.117 32.626 1.00 32.80 557 N TYR 598 15.376 57.571 30.312 1.00 21.10 558 CA TYR 598 16.362 56.521 30.034 1.00 23.73 559 C TYR 598 16.240 55.998 28.622 1.00 21.41 560 O TYR 598 17.233 55.689 27.968 1.00 24.76 561 CB TYR 598 16.150 55.309 30.946 1.00 22.41 562 CG TYR 598 16.647 55.443 32.367 1.00 21.14 563 CD1 TYR 598 17.195 56.628 32.840 1.00 22.56 564 CD2 TYR 598 16.589 54.356 33.230 1.00 25.54 565 CE1 TYR 598 17.682 56.729 34.154 1.00 27.58 566 CE2 TYR 598 17.068 54.442 34.533 1.00 23.54 567 CZ TYR 598 17.612 55.626 34.989 1.00 22.36 568 OH TYR 598 18.085 55.737 36.276 1.00 29.42 569 N SER 599 15.014 55.934 28.138 1.00 19.69 570 CA SER 599 14.784 55.299 26.849 1.00 21.05 571 C SER 599 14.475 56.110 25.608 1.00 20.67 572 O SER 599 14.363 55.519 24.520 1.00 17.40 573 CB SER 599 13.657 54.283 27.020 1.00 24.21 574 OG SER 599 12.387 54.913 27.142 1.00 27.35 575 N TRP 600 14.371 57.430 25.724 1.00 17.55 576 CA TRP 600 13.998 58.207 24.546 1.00 21.93 577 C TRP 600 14.874 57.931 23.320 1.00 18.91 578 O TRP 600 14.350 57.773 22.223 1.00 20.07 579 CB TRP 600 13.972 59.717 24.836 1.00 22.52 580 CG TRP 600 15.298 60.318 25.168 1.00 23.08 581 CD1 TRP 600 15.904 60.348 26.389 1.00 28.21 582 CD2 TRP 600 16.200 60.938 24.252 1.00 24.51 583 NE1 TRP 600 17.137 60.953 26.292 1.00 25.19 584 CE2 TRP 600 17.342 61.325 24.989 1.00 26.64 585 CE3 TRP 600 16.154 61.203 22.880 1.00 25.75 586 CZ2 TRP 600 18.442 61.969 24.396 1.00 29.86 587 CZ3 TRP 600 17.249 61.843 22.288 1.00 32.59 588 CH2 TRP 600 18.375 62.218 23.048 1.00 30.85 589 N MET 601 16.191 57.861 23.495 1.00 21.38 590 CA MET 601 17.087 57.622 22.352 1.00 18.69 591 C MET 601 16.823 56.265 21.715 1.00 23.20 592 O MET 601 16.790 56.138 20.478 1.00 21.19 593 CB MET 601 18.553 57.684 22.783 1.00 21.49 594 CG MET 601 19.522 57.518 21.611 1.00 22.22 595 SD MET 601 19.630 59.001 20.532 1.00 27.03 596 CE MET 601 20.664 60.086 21.623 1.00 26.64 597 N PHE 602 16.668 55.248 22.557 1.00 19.23 598 CA PHE 602 16.383 53.904 22.078 1.00 22.32 599 C PHE 602 15.085 53.867 21.295 1.00 20.68 600 O PHE 602 15.028 53.277 20.224 1.00 21.09 601 CB PHE 602 16.113 52.858 23.210 1.00 23.54 602 CG PHE 602 17.192 52.587 24.232 1.00 99.90 603 CD1 PHE 602 17.625 53.578 25.189 1.00 99.90 604 CD2 PHE 602 17.732 51.253 24.325 1.00 99.90 605 CE1 PHE 602 18.605 53.248 26.189 1.00 99.90 606 CE2 PHE 602 18.716 50.929 25.313 1.00 99.90 607 CZ PHE 602 19.158 51.927 26.246 1.00 99.90 608 N LEU 603 14.035 54.487 21.830 1.00 20.06 609 CA LEU 603 12.735 54.478 21.165 1.00 16.39 610 C LEU 603 12.804 55.201 19.831 1.00 18.68 611 O LEU 603 12.226 54.754 18.838 1.00 18.94 612 CB LEU 603 11.679 55.173 22.038 1.00 14.15 613 CG LEU 603 11.408 54.532 23.397 1.00 20.53 614 CD1 LEU 603 10.488 55.448 24.208 1.00 20.07 615 CD2 LEU 603 10.742 53.165 23.186 1.00 24.11 616 N MET 604 13.503 56.329 19.810 1.00 18.42 617 CA MET 604 13.597 57.094 18.587 1.00 19.21 618 C MET 604 14.437 56.424 17.504 1.00 19.93 619 O MET 604 14.071 56.492 16.322 1.00 23.09 620 CB MET 604 14.113 58.499 18.889 1.00 21.20 621 CG MET 604 13.084 59.331 19.684 1.00 21.45 622 SD MET 604 13.619 61.014 19.956 1.00 25.97 623 CE MET 604 12.389 61.557 21.170 1.00 26.52 624 N ALA 605 15.545 55.793 17.873 1.00 18.66 625 CA ALA 605 16.357 55.125 16.843 1.00 19.71 626 C ALA 605 15.628 53.865 16.343 1.00 22.38 627 O ALA 605 15.752 53.486 15.178 1.00 18.63 628 CB ALA 605 17.774 54.744 17.363 1.00 20.60 629 N PHE 606 14.871 53.230 17.233 1.00 18.16 630 CA PHE 606 14.092 52.032 16.886 1.00 20.65 631 C PHE 606 13.005 52.461 15.884 1.00 21.25 632 O PHE 606 12.762 51.773 14.879 1.00 23.39 633 CB PHE 606 13.479 51.439 18.173 1.00 19.84 634 CG PHE 606 13.048 49.979 18.055 1.00 22.22 635 CD1 PHE 606 13.982 48.980 17.790 1.00 22.72 636 CD2 PHE 606 11.719 49.613 18.255 1.00 23.08 637 CE1 PHE 606 13.609 47.639 17.726 1.00 23.74 638 CE2 PHE 606 11.325 48.274 18.196 1.00 24.95 639 CZ PHE 606 12.266 47.287 17.930 1.00 22.67 640 N ALA 607 12.352 53.591 16.160 1.00 18.00 641 CA ALA 607 11.335 54.114 15.266 1.00 19.15 642 C ALA 607 11.932 54.472 13.914 1.00 19.60 643 O ALA 607 11.307 54.266 12.866 1.00 17.94 644 CB ALA 607 10.674 55.315 15.963 1.00 99.90 645 N LEU 608 13.135 55.044 13.939 1.00 18.18 646 CA LEU 608 13.841 55.382 12.710 1.00 18.82 647 C LEU 608 14.041 54.100 11.907 1.00 20.32 648 O LEU 608 13.869 54.087 10.671 1.00 21.06 649 CB LEU 608 15.201 55.995 13.046 1.00 18.85 650 CG LEU 608 16.256 56.031 11.928 1.00 15.12 651 CD1 LEU 608 15.824 56.992 10.845 1.00 21.31 652 CD2 LEU 608 17.592 56.443 12.524 1.00 22.01 653 N GLY 609 14.406 53.031 12.610 1.00 19.32 654 CA GLY 609 14.642 51.749 11.967 1.00 22.15 655 C GLY 609 13.388 51.267 11.274 1.00 22.09 656 O GLY 609 13.404 50.859 10.095 1.00 18.52 657 N TRP 610 12.274 51.326 11.995 1.00 18.65 658 CA TRP 610 11.011 50.885 11.424 1.00 21.70 659 C TRP 610 10.602 51.712 10.189 1.00 20.69 660 O TRP 610 10.218 51.156 9.162 1.00 20.73 661 CB TRP 610 9.911 50.926 12.493 1.00 19.80 662 CG TRP 610 8.584 50.462 11.980 1.00 20.60 663 CD1 TRP 610 7.541 51.236 11.588 1.00 26.35 664 CD2 TRP 610 8.204 49.104 11.712 1.00 22.75 665 NE1 TRP 610 6.527 50.452 11.086 1.00 25.80 666 CE2 TRP 610 6.909 49.137 11.151 1.00 27.72 667 CE3 TRP 610 8.835 47.870 11.890 1.00 24.76 668 CZ2 TRP 610 6.223 47.971 10.759 1.00 28.33 669 CZ3 TRP 610 8.154 46.703 11.502 1.00 25.79 670 CH2 TRP 610 6.862 46.771 10.944 1.00 23.99 671 N ARG 611 10.686 53.038 10.273 1.00 20.81 672 CA ARG 611 10.301 53.868 9.132 1.00 18.86 673 C ARG 611 11.209 53.618 7.926 1.00 18.44 674 O ARG 611 10.747 53.594 6.783 1.00 20.30 675 CB ARG 611 10.341 55.357 9.493 1.00 18.28 676 CG ARG 611 9.298 55.794 10.543 1.00 20.05 677 CD ARG 611 9.320 57.317 10.695 1.00 25.08 678 NE ARG 611 10.593 57.831 11.202 1.00 20.13 679 CZ ARG 611 10.944 57.862 12.483 1.00 22.33 680 NH1 ARG 611 10.128 57.409 13.478 1.00 22.73 681 NH2 ARG 611 12.160 58.356 12.800 1.00 19.31 682 N SER 612 12.490 53.431 8.187 1.00 20.91 683 CA SER 612 13.459 53.185 7.117 1.00 18.59 684 C SER 612 13.126 51.856 6.432 1.00 24.76 685 O SER 612 13.088 51.761 5.208 1.00 19.96 686 CB SER 612 14.869 53.159 7.709 1.00 19.66 687 OG SER 612 15.287 54.391 8.280 1.00 23.01 688 N TYR 613 12.852 50.847 7.248 1.00 20.64 689 CA TYR 613 12.468 49.520 6.762 1.00 21.51 690 C TYR 613 11.193 49.603 5.909 1.00 20.49 691 O TYR 613 11.166 49.176 4.749 1.00 20.85 692 CB TYR 613 12.255 48.625 7.993 1.00 20.88 693 CG TYR 613 11.481 47.341 7.799 1.00 24.41 694 CD1 TYR 613 11.853 46.392 6.843 1.00 24.71 695 CD2 TYR 613 10.448 47.022 8.672 1.00 22.00 696 CE1 TYR 613 11.208 45.137 6.787 1.00 21.58 697 CE2 TYR 613 9.812 45.792 8.622 1.00 21.74 698 CZ TYR 613 10.203 44.853 7.691 1.00 24.16 699 OH TYR 613 9.579 43.627 7.637 1.00 22.86 700 N ARG 614 10.147 50.203 6.467 1.00 19.61 701 CA ARG 614 8.859 50.302 5.779 1.00 20.88 702 C ARG 614 8.783 51.149 4.525 1.00 25.83 703 O ARG 614 8.173 50.737 3.535 1.00 23.20 704 CB ARG 614 7.789 50.821 6.744 1.00 26.26 705 CG ARG 614 7.402 49.864 7.838 1.00 29.74 706 CD ARG 614 6.455 48.756 7.353 1.00 34.33 707 NE ARG 614 6.095 47.866 8.496 1.00 99.90 708 CZ ARG 614 5.290 46.810 8.424 1.00 99.90 709 NH1 ARG 614 5.065 46.135 9.507 1.00 99.90 710 NH2 ARG 614 4.714 46.415 7.324 1.00 99.90 711 N GLN 615 9.397 52.326 4.564 1.00 20.34 712 CA GLN 615 9.314 53.278 3.458 1.00 25.32 713 C GLN 615 10.398 53.227 2.392 1.00 24.30 714 O GLN 615 10.153 53.590 1.243 1.00 23.64 715 CB GLN 615 9.274 54.708 4.027 1.00 25.43 716 CG GLN 615 9.138 55.864 2.982 1.00 99.90 717 CD GLN 615 9.152 57.318 3.470 1.00 99.90 718 OE1 GLN 615 9.089 58.249 2.682 1.00 99.90 719 NE2 GLN 615 9.259 57.578 4.749 1.00 99.90 720 N SER 616 11.596 52.791 2.759 1.00 24.39 721 CA SER 616 12.680 52.765 1.789 1.00 25.76 722 C SER 616 13.443 51.452 1.809 1.00 24.92 723 O SER 616 14.609 51.399 1.451 1.00 27.56 724 CB SER 616 13.650 53.978 2.014 1.00 27.85 725 OG SER 616 14.409 53.867 3.223 1.00 99.90 726 N SER 617 12.763 50.384 2.217 1.00 22.68 727 CA SER 617 13.365 49.052 2.280 1.00 24.24 728 C SER 617 14.686 48.997 3.021 1.00 22.19 729 O SER 617 15.547 48.160 2.721 1.00 24.35 730 CB SER 617 13.526 48.483 0.862 1.00 22.79 731 OG SER 617 12.294 48.353 0.151 1.00 24.02 732 N ALA 618 14.827 49.883 4.011 1.00 20.76 733 CA ALA 618 16.026 49.916 4.830 1.00 21.80 734 C ALA 618 17.254 50.449 4.123 1.00 20.80 735 O ALA 618 18.352 50.403 4.676 1.00 25.34 736 CB ALA 618 16.235 48.506 5.409 1.00 99.90 737 N ASN 619 17.069 50.990 2.928 1.00 23.07 738 CA ASN 619 18.203 51.479 2.156 1.00 23.42 739 C ASN 619 18.560 52.962 2.319 1.00 25.60 740 O ASN 619 19.512 53.440 1.703 1.00 23.56 741 CB ASN 619 17.987 51.138 0.680 1.00 25.32 742 CG ASN 619 17.774 49.661 0.332 1.00 99.90 743 OD1 ASN 619 16.665 49.194 0.123 1.00 99.90 744 ND2 ASN 619 18.813 48.871 0.281 1.00 99.90 745 N LEU 620 17.787 53.687 3.121 1.00 21.96 746 CA LEU 620 18.074 55.094 3.425 1.00 22.20 747 C LEU 620 17.560 55.257 4.857 1.00 24.08 748 O LEU 620 16.807 54.408 5.327 1.00 21.84 749 CB LEU 620 17.311 56.048 2.499 1.00 23.95 750 CG LEU 620 17.531 55.912 0.968 1.00 99.90 751 CD1 LEU 620 16.772 57.020 0.225 1.00 99.90 752 CD2 LEU 620 19.018 55.951 0.576 1.00 99.90 753 N LEU 621 17.985 56.311 5.552 1.00 21.78 754 CA LEU 621 17.505 56.553 6.924 1.00 22.28 755 C LEU 621 16.356 57.545 6.837 1.00 20.07 756 O LEU 621 16.541 58.727 6.544 1.00 21.05 757 CB LEU 621 18.630 57.076 7.826 1.00 21.10 758 CG LEU 621 19.759 56.060 8.074 1.00 24.71 759 CD1 LEU 621 20.794 56.627 9.017 1.00 26.09 760 CD2 LEU 621 19.174 54.777 8.653 1.00 23.43 761 N CYS 622 15.154 57.041 7.070 1.00 20.52 762 CA CYS 622 13.950 57.844 6.975 1.00 17.48 763 C CYS 622 13.647 58.516 8.327 1.00 21.46 764 O CYS 622 12.783 58.069 9.066 1.00 18.14 765 CB CYS 622 12.729 57.025 6.493 1.00 20.38 766 SG CYS 622 12.923 56.304 4.826 1.00 99.90 767 N PHE 623 14.377 59.583 8.644 1.00 20.19 768 CA PHE 623 14.147 60.288 9.903 1.00 22.33 769 C PHE 623 12.734 60.881 9.946 1.00 19.77 770 O PHE 623 12.036 60.799 10.953 1.00 20.69 771 CB PHE 623 15.209 61.386 10.109 1.00 17.81 772 CG PHE 623 16.565 60.855 10.420 1.00 19.78 773 CD1 PHE 623 17.463 60.544 9.409 1.00 26.89 774 CD2 PHE 623 16.942 60.616 11.737 1.00 21.49 775 CE1 PHE 623 18.726 59.999 9.722 1.00 24.89 776 CE2 PHE 623 18.193 60.073 12.051 1.00 21.92 777 CZ PHE 623 19.087 59.766 11.043 1.00 25.29 778 N ALA 624 12.311 61.478 8.846 1.00 18.84 779 CA ALA 624 10.976 62.054 8.755 1.00 18.94 780 C ALA 624 10.706 62.148 7.259 1.00 23.24 781 O ALA 624 11.621 61.956 6.458 1.00 21.88 782 CB ALA 624 10.948 63.442 9.399 1.00 19.00 783 N PRO 625 9.452 62.382 6.864 1.00 24.08 784 CA PRO 625 9.122 62.493 5.441 1.00 22.75 785 C PRO 625 9.897 63.631 4.757 1.00 31.17 786 O PRO 625 10.189 63.558 3.560 1.00 27.19 787 CB PRO 625 7.618 62.742 5.476 1.00 23.42 788 CG PRO 625 7.198 61.973 6.719 1.00 29.68 789 CD PRO 625 8.225 62.532 7.668 1.00 19.66 790 N ASP 626 10.240 64.671 5.514 1.00 24.25 791 CA ASP 626 10.984 65.801 4.951 1.00 30.35 792 C ASP 626 12.470 65.758 5.305 1.00 28.45 793 O ASP 626 13.216 66.724 5.082 1.00 31.54 794 CB ASP 626 10.362 67.106 5.439 1.00 33.03 795 CG ASP 626 10.455 67.270 6.945 1.00 42.61 796 OD1 ASP 626 10.274 66.273 7.681 1.00 37.30 797 OD2 ASP 626 10.687 68.409 7.395 1.00 39.66 798 N LEU 627 12.907 64.627 5.844 1.00 25.42 799 CA LEU 627 14.290 64.464 6.238 1.00 23.61 800 C LEU 627 14.689 62.992 6.078 1.00 25.27 801 O LEU 627 14.650 62.200 7.018 1.00 21.60 802 CB LEU 627 14.465 64.921 7.686 1.00 25.81 803 CG LEU 627 15.903 65.214 8.098 1.00 26.41 804 CD1 LEU 627 16.471 66.222 7.110 1.00 37.20 805 CD2 LEU 627 15.944 65.796 9.499 1.00 23.25 806 N ILE 628 15.038 62.634 4.849 1.00 20.00 807 CA ILE 628 15.447 61.288 4.510 1.00 21.82 808 C ILE 628 16.926 61.365 4.132 1.00 26.37 809 O ILE 628 17.280 62.120 3.233 1.00 27.10 810 CB ILE 628 14.659 60.791 3.287 1.00 19.86 811 CG1 ILE 628 13.160 60.854 3.576 1.00 23.93 812 CG2 ILE 628 15.107 59.369 2.935 1.00 26.69 813 CD1 ILE 628 12.264 60.752 2.345 1.00 22.62 814 N ILE 629 17.781 60.593 4.797 1.00 24.00 815 CA ILE 629 19.203 60.626 4.478 1.00 30.39 816 C ILE 629 19.745 59.395 3.756 1.00 28.22 817 O ILE 629 19.446 58.251 4.116 1.00 27.38 818 CB ILE 629 19.971 60.933 5.814 1.00 27.74 819 CG2 ILE 629 21.443 61.321 5.592 1.00 99.90 820 CG1 ILE 629 19.354 62.070 6.698 1.00 99.90 821 CD1 ILE 629 19.296 63.491 6.094 1.00 99.90 822 N ASN 630 20.560 59.665 2.739 1.00 37.87 823 CA ASN 630 21.239 58.635 1.955 1.00 34.28 824 C ASN 630 22.728 58.921 2.135 1.00 40.43 825 O ASN 630 23.105 59.961 2.699 1.00 32.88 826 CB ASN 630 20.868 58.724 0.473 1.00 43.78 827 CG ASN 630 21.147 60.091 −0.113 1.00 39.05 828 OD1 ASN 630 22.203 60.674 0.123 1.00 56.25 829 ND2 ASN 630 20.136 60.626 −0.936 1.00 55.74 830 N GLU 631 23.563 58.000 1.660 1.00 37.34 831 CA GLU 631 25.015 58.123 1.773 1.00 41.84 832 C GLU 631 25.558 59.475 1.335 1.00 36.02 833 O GLU 631 26.437 60.024 1.991 1.00 37.52 834 CB GLU 631 25.716 57.026 0.967 1.00 43.26 835 CG GLU 631 25.473 55.592 1.439 1.00 53.06 836 CD GLU 631 24.088 55.065 1.099 1.00 52.18 837 OE1 GLU 631 23.252 55.830 0.573 1.00 55.65 838 OE2 GLU 631 23.838 53.869 1.359 1.00 59.59 839 N GLN 632 25.040 60.004 0.229 1.00 37.37 840 CA GLN 632 25.483 61.297 −0.301 1.00 41.31 841 C GLN 632 25.334 62.468 0.673 1.00 44.67 842 O GLN 632 26.122 63.416 0.642 1.00 39.36 843 CB GLN 632 24.710 61.641 −1.575 1.00 39.63 844 CG GLN 632 24.887 60.656 −2.720 1.00 54.67 845 CD GLN 632 23.944 60.939 −3.875 1.00 54.04 846 OE1 GLN 632 24.051 61.964 −4.552 1.00 65.04 847 NE2 GLN 632 22.945 59.973 −4.120 1.00 58.37 848 N ARG 633 24.327 62.401 1.538 1.00 42.38 849 CA ARG 633 24.072 63.483 2.483 1.00 46.01 850 C ARG 633 24.797 63.327 3.817 1.00 44.06 851 O ARG 633 24.707 64.194 4.690 1.00 43.28 852 CB ARG 633 22.560 63.614 2.701 1.00 45.62 853 CG ARG 633 21.804 63.732 1.385 1.00 51.99 854 CD ARG 633 20.303 63.885 1.551 1.00 54.00 855 NE ARG 633 19.923 65.164 2.148 1.00 62.20 856 CZ ARG 633 18.664 65.565 2.312 1.00 62.82 857 NH1 ARG 633 17.623 64.842 1.808 1.00 63.08 858 NH2 ARG 633 18.318 66.680 2.975 1.00 64.33 859 N MET 634 25.524 62.231 3.972 1.00 42.60 860 CA MET 634 26.267 61.991 5.200 1.00 44.82 861 C MET 634 27.734 62.253 4.897 1.00 44.81 862 O MET 634 28.533 61.322 4.802 1.00 41.79 863 CB MET 634 26.074 60.546 5.653 1.00 47.11 864 CG MET 634 24.619 60.166 5.850 1.00 38.54 865 SD MET 634 24.425 58.402 6.144 1.00 40.15 866 CE MET 634 22.638 58.288 6.218 1.00 40.02 867 N THR 635 28.077 63.525 4.733 1.00 45.90 868 CA THR 635 29.448 63.911 4.417 1.00 49.64 869 C THR 635 30.366 63.686 5.604 1.00 52.38 870 O THR 635 31.373 62.981 5.505 1.00 56.13 871 CB THR 635 29.493 65.382 4.014 1.00 52.46 872 OG1 THR 635 28.707 65.604 2.851 1.00 99.90 873 CG2 THR 635 30.883 65.951 3.656 1.00 99.90 874 N LEU 636 30.007 64.308 6.721 1.00 54.04 875 CA LEU 636 30.756 64.222 7.970 1.00 54.00 876 C LEU 636 31.118 62.774 8.280 1.00 52.73 877 O LEU 636 30.238 61.939 8.474 1.00 52.98 878 CB LEU 636 30.018 64.862 9.170 1.00 61.18 879 CG LEU 636 30.886 65.075 10.440 1.00 99.90 880 CD1 LEU 636 31.840 66.285 10.304 1.00 99.90 881 CD2 LEU 636 30.007 65.206 11.701 1.00 99.90 882 N PRO 637 32.410 62.469 8.330 1.00 47.20 883 CA PRO 637 32.837 61.103 8.611 1.00 47.93 884 C PRO 637 32.365 60.555 9.969 1.00 45.20 885 O PRO 637 32.004 59.376 10.065 1.00 41.96 886 CB PRO 637 34.365 60.995 8.489 1.00 47.55 887 CG PRO 637 34.792 62.388 8.982 1.00 99.90 888 CD PRO 637 33.765 63.328 8.343 1.00 99.90 889 N CYS 638 32.359 61.394 11.012 1.00 41.56 890 CA CYS 638 31.923 60.938 12.337 1.00 34.71 891 C CYS 638 30.419 60.645 12.344 1.00 33.35 892 O CYS 638 29.985 59.654 12.927 1.00 30.89 893 CB CYS 638 32.341 61.841 13.519 1.00 36.41 894 SG CYS 638 31.647 63.515 13.583 1.00 99.90 895 N MET 639 29.644 61.502 11.684 1.00 32.63 896 CA MET 639 28.196 61.332 11.615 1.00 35.71 897 C MET 639 27.821 60.152 10.712 1.00 35.32 898 O MET 639 26.883 59.415 11.002 1.00 33.54 899 CB MET 639 27.482 62.566 11.004 1.00 42.64 900 CG MET 639 25.996 62.404 10.638 1.00 99.90 901 SD MET 639 25.346 63.899 9.804 1.00 99.90 902 CE MET 639 24.091 63.111 8.739 1.00 99.90 903 N TYR 640 28.560 59.979 9.620 1.00 31.90 904 CA TYR 640 28.315 58.858 8.708 1.00 28.99 905 C TYR 640 28.560 57.587 9.490 1.00 25.10 906 O TYR 640 27.802 56.627 9.404 1.00 29.55 907 CB TYR 640 29.281 58.918 7.518 1.00 37.34 908 CG TYR 640 29.171 57.750 6.560 1.00 40.29 909 CD1 TYR 640 28.014 57.544 5.805 1.00 40.54 910 CD2 TYR 640 30.233 56.862 6.397 1.00 42.80 911 CE1 TYR 640 27.918 56.487 4.913 1.00 42.21 912 CE2 TYR 640 30.148 55.798 5.504 1.00 45.44 913 CZ TYR 640 28.988 55.618 4.762 1.00 44.14 914 OH TYR 640 28.896 54.572 3.871 1.00 48.25 915 N ASP 641 29.622 57.572 10.282 1.00 24.54 916 CA ASP 641 29.907 56.378 11.043 1.00 25.44 917 C ASP 641 28.766 56.107 12.019 1.00 28.08 918 O ASP 641 28.423 54.954 12.269 1.00 31.55 919 CB ASP 641 31.224 56.521 11.805 1.00 32.47 920 CG ASP 641 31.748 55.265 12.517 1.00 99.90 921 OD1 ASP 641 32.268 55.294 13.623 1.00 99.90 922 OD2 ASP 641 31.547 54.123 11.794 1.00 99.90 923 N GLN 642 28.183 57.165 12.575 1.00 25.12 924 CA GLN 642 27.081 56.967 13.514 1.00 25.95 925 C GLN 642 25.853 56.449 12.766 1.00 27.16 926 O GLN 642 25.099 55.631 13.289 1.00 29.13 927 CB GLN 642 26.776 58.283 14.226 1.00 32.01 928 CG GLN 642 25.534 58.198 15.118 1.00 99.90 929 CD GLN 642 25.367 59.502 15.876 1.00 99.90 930 OE1 GLN 642 25.084 59.490 17.059 1.00 99.90 931 NE2 GLN 642 25.556 60.682 15.111 1.00 99.90 932 N CYS 643 25.641 56.940 11.549 1.00 26.93 933 CA CYS 643 24.514 56.484 10.748 1.00 28.14 934 C CYS 643 24.633 55.008 10.390 1.00 24.65 935 O CYS 643 23.628 54.295 10.365 1.00 25.73 936 CB CYS 643 24.377 57.324 9.477 1.00 24.73 937 SG CYS 643 23.765 59.023 9.748 1.00 32.75 938 N LYS 644 25.853 54.544 10.110 1.00 25.25 939 CA LYS 644 26.062 53.132 9.792 1.00 26.29 940 C LYS 644 25.682 52.271 10.978 1.00 27.01 941 O LYS 644 25.217 51.133 10.827 1.00 27.73 942 CB LYS 644 27.522 52.862 9.434 1.00 28.72 943 CG LYS 644 27.792 51.395 9.014 1.00 99.90 944 CD LYS 644 29.258 51.072 8.711 1.00 99.90 945 CE LYS 644 29.388 49.579 8.381 1.00 99.90 946 NZ LYS 644 30.760 49.297 7.922 1.00 99.90 947 N HIS 645 25.914 52.808 12.169 1.00 28.68 948 CA HIS 645 25.574 52.111 13.399 1.00 27.55 949 C HIS 645 24.058 52.056 13.507 1.00 20.19 950 O HIS 645 23.490 51.021 13.856 1.00 28.87 951 CB HIS 645 26.107 52.749 14.715 1.00 37.30 952 CG HIS 645 27.612 52.692 14.796 1.00 99.90 953 ND1 HIS 645 28.464 52.435 13.772 1.00 99.90 954 CD2 HIS 645 28.375 52.877 15.984 1.00 99.90 955 CE1 HIS 645 29.707 52.477 14.312 1.00 99.90 956 NE2 HIS 645 29.741 52.753 15.701 1.00 99.90 957 N MET 646 23.410 53.174 13.213 1.00 20.28 958 CA MET 646 21.953 53.226 13.270 1.00 23.80 959 C MET 646 21.364 52.299 12.209 1.00 25.24 960 O MET 646 20.358 51.634 12.444 1.00 23.42 961 CB MET 646 21.457 54.660 13.040 1.00 23.19 962 CG MET 646 21.841 55.620 14.177 1.00 25.74 963 SD MET 646 21.014 57.221 13.996 1.00 29.64 964 CE MET 646 21.961 57.963 12.711 1.00 40.66 965 N LEU 647 22.017 52.247 11.053 1.00 27.17 966 CA LEU 647 21.560 51.430 9.929 1.00 27.11 967 C LEU 647 21.425 49.945 10.251 1.00 28.77 968 O LEU 647 20.705 49.207 9.571 1.00 26.96 969 CB LEU 647 22.502 51.592 8.740 1.00 27.64 970 CG LEU 647 22.725 53.021 8.174 1.00 99.90 971 CD1 LEU 647 23.610 52.959 6.921 1.00 99.90 972 CD2 LEU 647 21.407 53.741 7.842 1.00 99.90 973 N TYR 648 22.122 49.506 11.291 1.00 27.01 974 CA TYR 648 22.068 48.111 11.700 1.00 29.15 975 C TYR 648 20.655 47.659 12.025 1.00 27.44 976 O TYR 648 20.301 46.504 11.793 1.00 26.00 977 CB TYR 648 22.937 47.884 12.928 1.00 27.84 978 CG TYR 648 24.436 48.162 12.771 1.00 99.90 979 CD1 TYR 648 24.976 49.355 13.263 1.00 99.90 980 CD2 TYR 648 25.270 47.239 12.134 1.00 99.90 981 CE1 TYR 648 26.333 49.624 13.113 1.00 99.90 982 CE2 TYR 648 26.628 47.512 11.984 1.00 99.90 983 CZ TYR 648 27.158 48.702 12.474 1.00 99.90 984 OH TYR 648 28.490 48.967 12.323 1.00 99.90 985 N VAL 649 19.852 48.556 12.584 1.00 23.42 986 CA VAL 649 18.493 48.186 12.934 1.00 25.19 987 C VAL 649 17.612 47.883 11.712 1.00 22.21 988 O VAL 649 17.038 46.798 11.627 1.00 28.86 989 CB VAL 649 17.786 49.291 13.791 1.00 25.31 990 CG1 VAL 649 18.566 49.652 15.080 1.00 99.90 991 CG2 VAL 649 16.350 48.878 14.193 1.00 99.90 992 N SER 650 17.484 48.821 10.756 1.00 22.89 993 CA SER 650 16.645 48.538 9.576 1.00 26.67 994 C SER 650 17.123 47.268 8.877 1.00 25.60 995 O SER 650 16.329 46.505 8.316 1.00 25.13 996 CB SER 650 16.871 49.767 8.690 1.00 22.17 997 OG SER 650 18.194 49.823 8.144 1.00 99.90 998 N SER 651 18.438 47.055 8.909 1.00 29.12 999 CA SER 651 19.039 45.877 8.287 1.00 28.65 1000 C SER 651 18.555 44.601 8.929 1.00 30.22 1001 O SER 651 18.250 43.641 8.228 1.00 28.51 1002 CB SER 651 20.571 45.944 8.347 1.00 33.89 1003 OG SER 651 21.083 45.792 9.676 1.00 99.90 1004 N GLU 652 18.477 44.579 10.256 1.00 25.11 1005 CA GLU 652 17.997 43.392 10.939 1.00 25.25 1006 C GLU 652 16.513 43.250 10.723 1.00 21.49 1007 O GLU 652 16.022 42.128 10.673 1.00 25.66 1008 CB GLU 652 18.332 43.429 12.437 1.00 28.40 1009 CG GLU 652 19.812 43.255 12.685 1.00 41.59 1010 CD GLU 652 20.311 41.886 12.215 1.00 49.95 1011 OE1 GLU 652 19.494 40.940 12.148 1.00 44.78 1012 OE2 GLU 652 21.523 41.746 11.929 1.00 51.07 1013 N LEU 653 15.810 44.381 10.587 1.00 24.33 1014 CA LEU 653 14.366 44.377 10.349 1.00 26.06 1015 C LEU 653 14.098 43.720 9.012 1.00 26.07 1016 O LEU 653 13.183 42.919 8.888 1.00 22.03 1017 CB LEU 653 13.777 45.803 10.351 1.00 22.64 1018 CG LEU 653 13.974 46.674 11.621 1.00 99.90 1019 CD1 LEU 653 13.225 48.005 11.469 1.00 99.90 1020 CD2 LEU 653 13.515 45.964 12.905 1.00 99.90 1021 N HIS 654 14.917 44.058 8.021 1.00 26.08 1022 CA HIS 654 14.784 43.475 6.679 1.00 24.64 1023 C HIS 654 15.102 41.986 6.716 1.00 26.29 1024 O HIS 654 14.350 41.166 6.183 1.00 28.56 1025 CB HIS 654 15.741 44.168 5.693 1.00 28.11 1026 CG HIS 654 15.011 44.831 4.562 1.00 99.90 1027 ND1 HIS 654 13.630 44.845 4.380 1.00 99.90 1028 CD2 HIS 654 15.664 45.519 3.549 1.00 99.90 1029 CE1 HIS 654 13.555 45.565 3.245 1.00 99.90 1030 NE2 HIS 654 14.716 46.000 2.684 1.00 99.90 1031 N ARG 655 16.215 41.635 7.356 1.00 22.16 1032 CA ARG 655 16.655 40.248 7.453 1.00 28.14 1033 C ARG 655 15.632 39.355 8.165 1.00 29.30 1034 O ARG 655 15.288 38.265 7.691 1.00 29.13 1035 CB ARG 655 18.000 40.212 8.187 1.00 31.67 1036 CG ARG 655 18.709 38.870 8.246 1.00 41.13 1037 CD ARG 655 19.991 38.988 9.093 1.00 46.76 1038 NE ARG 655 20.696 37.673 9.123 1.00 99.90 1039 CZ ARG 655 21.836 37.426 9.761 1.00 99.90 1040 NH1 ARG 655 22.334 36.232 9.690 1.00 99.90 1041 NH2 ARG 655 22.482 38.320 10.456 1.00 99.90 1042 N LEU 656 15.137 39.816 9.305 1.00 29.04 1043 CA LEU 656 14.166 39.042 10.067 1.00 27.03 1044 C LEU 656 12.717 39.206 9.606 1.00 24.56 1045 O LEU 656 11.843 38.435 10.014 1.00 25.98 1046 CB LEU 656 14.250 39.420 11.556 1.00 30.03 1047 CG LEU 656 15.510 39.055 12.345 1.00 36.08 1048 CD1 LEU 656 15.367 39.505 13.786 1.00 28.22 1049 CD2 LEU 656 15.715 37.556 12.295 1.00 33.46 1050 N GLN 657 12.466 40.202 8.760 1.00 24.63 1051 CA GLN 657 11.116 40.499 8.294 1.00 24.29 1052 C GLN 657 10.156 40.706 9.479 1.00 28.28 1053 O GLN 657 9.089 40.084 9.572 1.00 26.02 1054 CB GLN 657 10.603 39.400 7.354 1.00 31.81 1055 CG GLN 657 11.444 39.296 6.098 1.00 34.45 1056 CD GLN 657 10.824 38.430 5.002 1.00 43.12 1057 OE1 GLN 657 11.432 38.232 3.941 1.00 48.46 1058 NE2 GLN 657 9.566 37.825 5.223 1.00 38.30 1059 N VAL 658 10.561 41.594 10.384 1.00 23.00 1060 CA VAL 658 9.762 41.941 11.568 1.00 23.27 1061 C VAL 658 8.393 42.492 11.169 1.00 20.62 1062 O VAL 658 8.270 43.299 10.243 1.00 24.25 1063 CB VAL 658 10.506 42.989 12.436 1.00 22.34 1064 CG1 VAL 658 9.623 43.484 13.580 1.00 22.21 1065 CG2 VAL 658 11.756 42.374 12.981 1.00 20.16 1066 N SER 659 7.358 42.043 11.871 1.00 21.62 1067 CA SER 659 6.014 42.485 11.562 1.00 22.92 1068 C SER 659 5.624 43.697 12.393 1.00 21.08 1069 O SER 659 6.230 43.974 13.424 1.00 22.56 1070 CB SER 659 5.014 41.364 11.837 1.00 23.84 1071 OG SER 659 4.896 41.029 13.214 1.00 27.14 1072 N TYR 660 4.616 44.417 11.921 1.00 22.79 1073 CA TYR 660 4.110 45.589 12.619 1.00 26.53 1074 C TYR 660 3.729 45.186 14.046 1.00 24.03 1075 O TYR 660 4.017 45.904 14.994 1.00 23.00 1076 CB TYR 660 2.883 46.138 11.863 1.00 26.89 1077 CG TYR 660 3.117 46.616 10.426 1.00 99.90 1078 CD1 TYR 660 2.748 45.797 9.353 1.00 99.90 1079 CD2 TYR 660 3.703 47.859 10.174 1.00 99.90 1080 CE1 TYR 660 2.970 46.214 8.044 1.00 99.90 1081 CE2 TYR 660 3.924 48.275 8.863 1.00 99.90 1082 CZ TYR 660 3.557 47.453 7.801 1.00 99.90 1083 OH TYR 660 3.778 47.863 6.516 1.00 99.90 1084 N GLU 661 3.096 44.023 14.191 1.00 24.42 1085 CA GLU 661 2.660 43.541 15.509 1.00 24.69 1086 C GLU 661 3.838 43.258 16.431 1.00 21.73 1087 O GLU 661 3.771 43.539 17.622 1.00 23.19 1088 CB GLU 661 1.819 42.269 15.378 1.00 27.58 1089 CG GLU 661 0.536 42.386 14.563 1.00 32.90 1090 CD GLU 661 0.776 42.657 13.079 1.00 38.95 1091 OE1 GLU 661 1.753 42.130 12.509 1.00 36.30 1092 OE2 GLU 661 −0.044 43.378 12.472 1.00 49.03 1093 N GLU 662 4.911 42.676 15.890 1.00 21.48 1094 CA GLU 662 6.097 42.398 16.697 1.00 20.83 1095 C GLU 662 6.795 43.702 17.061 1.00 20.85 1096 O GLU 662 7.246 43.876 18.182 1.00 23.00 1097 CB GLU 662 7.090 41.515 15.936 1.00 22.67 1098 CG GLU 662 6.640 40.056 15.739 1.00 25.39 1099 CD GLU 662 7.482 39.316 14.703 1.00 33.69 1100 OE1 GLU 662 8.114 39.980 13.843 1.00 30.03 1101 OE2 GLU 662 7.506 38.070 14.732 1.00 30.51 1102 N TYR 663 6.916 44.604 16.093 1.00 21.31 1103 CA TYR 663 7.573 45.888 16.342 1.00 22.08 1104 C TYR 663 6.893 46.682 17.474 1.00 21.29 1105 O TYR 663 7.564 47.277 18.327 1.00 20.03 1106 CB TYR 663 7.540 46.721 15.070 1.00 23.06 1107 CG TYR 663 7.851 48.167 15.290 1.00 22.01 1108 CD1 TYR 663 9.155 48.583 15.542 1.00 22.32 1109 CD2 TYR 663 6.831 49.110 15.260 1.00 23.62 1110 CE1 TYR 663 9.434 49.925 15.755 1.00 27.65 1111 CE2 TYR 663 7.101 50.458 15.474 1.00 28.88 1112 CZ TYR 663 8.402 50.863 15.722 1.00 22.16 1113 OH TYR 663 8.673 52.185 15.935 1.00 99.90 1114 N LEU 664 5.567 46.711 17.455 1.00 21.31 1115 CA LEU 664 4.806 47.451 18.468 1.00 23.49 1116 C LEU 664 5.083 46.979 19.900 1.00 26.91 1117 O LEU 664 5.233 47.802 20.808 1.00 20.81 1118 CB LEU 664 3.310 47.384 18.143 1.00 24.50 1119 CG LEU 664 2.922 48.148 16.864 1.00 23.57 1120 CD1 LEU 664 1.452 47.937 16.521 1.00 22.54 1121 CD2 LEU 664 3.191 49.647 17.087 1.00 27.51 1122 N CYS 665 5.147 45.662 20.101 1.00 22.87 1123 CA CYS 665 5.431 45.097 21.416 1.00 26.80 1124 C CYS 665 6.902 45.304 21.783 1.00 25.96 1125 O CYS 665 7.240 45.589 22.934 1.00 20.10 1126 CB CYS 665 5.124 43.601 21.428 1.00 27.46 1127 SG CYS 665 3.371 43.221 21.079 1.00 33.20 1128 N MET 666 7.789 45.143 20.810 1.00 18.27 1129 CA MET 666 9.187 45.349 21.107 1.00 20.73 1130 C MET 666 9.446 46.800 21.523 1.00 18.21 1131 O MET 666 10.282 47.056 22.376 1.00 20.04 1132 CB MET 666 10.033 44.979 19.899 1.00 23.28 1133 CG MET 666 9.931 43.517 19.514 1.00 26.12 1134 SD MET 666 10.766 43.239 17.916 1.00 30.71 1135 CE MET 666 12.364 43.447 18.420 1.00 17.04 1136 N LYS 667 8.730 47.750 20.934 1.00 22.26 1137 CA LYS 667 8.958 49.158 21.285 1.00 21.99 1138 C LYS 667 8.593 49.432 22.742 1.00 23.71 1139 O LYS 667 9.255 50.224 23.423 1.00 20.06 1140 CB LYS 667 8.175 50.091 20.342 1.00 24.02 1141 CG LYS 667 8.621 51.548 20.407 1.00 31.07 1142 CD LYS 667 8.217 52.309 19.139 1.00 38.28 1143 CE LYS 667 6.708 52.411 18.956 1.00 39.48 1144 NZ LYS 667 5.961 53.284 19.944 1.00 42.42 1145 N THR 668 7.549 48.768 23.231 1.00 20.18 1146 CA THR 668 7.158 48.951 24.623 1.00 19.22 1147 C THR 668 8.223 48.345 25.523 1.00 21.84 1148 O THR 668 8.587 48.917 26.548 1.00 21.05 1149 CB THR 668 5.822 48.260 24.936 1.00 19.35 1150 OG1 THR 668 4.778 48.814 24.146 1.00 99.90 1151 CG2 THR 668 5.314 48.380 26.389 1.00 99.90 1152 N LEU 669 8.733 47.181 25.140 1.00 19.81 1153 CA LEU 669 9.769 46.539 25.937 1.00 20.73 1154 C LEU 669 11.013 47.417 26.009 1.00 24.51 1155 O LEU 669 11.743 47.380 26.999 1.00 21.96 1156 CB LEU 669 10.104 45.149 25.370 1.00 21.13 1157 CG LEU 669 8.943 44.165 25.568 1.00 20.69 1158 CD1 LEU 669 9.239 42.871 24.849 1.00 23.72 1159 CD2 LEU 669 8.725 43.908 27.077 1.00 21.59 1160 N LEU 670 11.252 48.224 24.980 1.00 22.43 1161 CA LEU 670 12.400 49.122 25.007 1.00 24.57 1162 C LEU 670 12.195 50.225 26.025 1.00 22.02 1163 O LEU 670 13.144 50.636 26.677 1.00 23.56 1164 CB LEU 670 12.663 49.769 23.650 1.00 19.15 1165 CG LEU 670 13.473 49.023 22.615 1.00 31.93 1166 CD1 LEU 670 13.732 50.001 21.470 1.00 28.38 1167 CD2 LEU 670 14.807 48.532 23.219 1.00 26.52 1168 N LEU 671 10.962 50.710 26.138 1.00 18.07 1169 CA LEU 671 10.629 51.743 27.114 1.00 20.16 1170 C LEU 671 10.919 51.217 28.524 1.00 23.85 1171 O LEU 671 11.313 51.963 29.427 1.00 23.95 1172 CB LEU 671 9.144 52.087 27.013 1.00 21.07 1173 CG LEU 671 8.548 52.995 28.099 1.00 22.15 1174 CD1 LEU 671 9.240 54.359 28.086 1.00 21.62 1175 CD2 LEU 671 7.050 53.150 27.871 1.00 22.53 1176 N LEU 672 10.721 49.917 28.697 1.00 16.99 1177 CA LEU 672 10.891 49.261 29.979 1.00 21.87 1178 C LEU 672 12.190 48.477 30.038 1.00 24.10 1179 O LEU 672 12.282 47.519 30.799 1.00 24.64 1180 CB LEU 672 9.721 48.283 30.185 1.00 20.22 1181 CG LEU 672 8.317 48.845 29.941 1.00 27.92 1182 CD1 LEU 672 7.264 47.732 30.054 1.00 24.44 1183 CD2 LEU 672 8.030 49.964 30.943 1.00 21.00 1184 N SER 673 13.210 48.881 29.281 1.00 21.55 1185 CA SER 673 14.431 48.072 29.246 1.00 26.34 1186 C SER 673 15.616 48.473 30.129 1.00 21.48 1187 O SER 673 16.654 47.815 30.120 1.00 25.22 1188 CB SER 673 14.882 47.946 27.792 1.00 24.75 1189 OG SER 673 15.366 49.181 27.251 1.00 99.90 1190 N SER 674 15.446 49.532 30.903 1.00 20.94 1191 CA SER 674 16.501 50.026 31.780 1.00 23.18 1192 C SER 674 15.855 50.647 33.002 1.00 24.51 1193 O SER 674 14.884 51.395 32.875 1.00 20.61 1194 CB SER 674 17.349 51.117 31.062 1.00 27.14 1195 OG SER 674 16.627 52.336 30.852 1.00 99.90 1196 N VAL 675 16.377 50.324 34.183 1.00 23.20 1197 CA VAL 675 15.853 50.899 35.422 1.00 22.29 1198 C VAL 675 17.003 51.371 36.308 1.00 23.93 1199 O VAL 675 18.163 51.045 36.053 1.00 23.93 1200 CB VAL 675 14.995 49.884 36.192 1.00 24.86 1201 CG1 VAL 675 13.702 49.465 35.450 1.00 99.90 1202 CG2 VAL 675 14.532 50.309 37.613 1.00 99.90 1203 N PRO 676 16.699 52.154 37.350 1.00 23.63 1204 CA PRO 676 17.741 52.651 38.250 1.00 26.05 1205 C PRO 676 18.406 51.512 39.004 1.00 30.91 1206 O PRO 676 17.822 50.433 39.164 1.00 27.25 1207 CB PRO 676 16.969 53.583 39.189 1.00 28.62 1208 CG PRO 676 15.761 54.002 38.335 1.00 25.78 1209 CD PRO 676 15.387 52.647 37.791 1.00 28.72 1210 N LYS 677 19.632 51.754 39.460 1.00 31.80 1211 CA LYS 677 20.378 50.754 40.215 1.00 34.58 1212 C LYS 677 19.609 50.311 41.453 1.00 32.37 1213 O LYS 677 19.708 49.157 41.871 1.00 38.50 1214 CB LYS 677 21.745 51.314 40.633 1.00 34.68 1215 CG LYS 677 22.631 50.283 41.377 1.00 99.90 1216 CD LYS 677 23.976 50.826 41.868 1.00 99.90 1217 CE LYS 677 24.713 49.726 42.643 1.00 99.90 1218 NZ LYS 677 26.075 50.184 42.968 1.00 99.90 1219 N ASP 678 18.837 51.223 42.031 1.00 33.46 1220 CA ASP 678 18.058 50.899 43.219 1.00 35.43 1221 C ASP 678 16.645 50.442 42.859 1.00 37.02 1222 O ASP 678 15.809 50.203 43.734 1.00 34.87 1223 CB ASP 678 18.002 52.103 44.174 1.00 40.38 1224 CG ASP 678 17.367 51.860 45.551 1.00 99.90 1225 OD1 ASP 678 16.636 52.671 46.100 1.00 99.90 1226 OD2 ASP 678 17.688 50.639 46.076 1.00 99.90 1227 N GLY 679 16.380 50.302 41.565 1.00 32.49 1228 CA GLY 679 15.063 49.872 41.144 1.00 28.49 1229 C GLY 679 14.103 51.045 41.110 1.00 30.77 1230 O GLY 679 14.481 52.171 41.415 1.00 29.05 1231 N LEU 680 12.857 50.766 40.745 1.00 27.80 1232 CA LEU 680 11.812 51.772 40.643 1.00 31.88 1233 C LEU 680 10.938 51.781 41.896 1.00 30.49 1234 O LEU 680 10.871 50.788 42.614 1.00 28.71 1235 CB LEU 680 10.929 51.449 39.440 1.00 28.43 1236 CG LEU 680 11.569 51.477 38.052 1.00 31.10 1237 CD1 LEU 680 10.606 50.863 37.058 1.00 29.92 1238 CD2 LEU 680 11.928 52.921 37.667 1.00 27.76 1239 N LYS 681 10.251 52.892 42.141 1.00 33.09 1240 CA LYS 681 9.359 52.979 43.300 1.00 33.34 1241 C LYS 681 8.216 51.968 43.117 1.00 37.41 1242 O LYS 681 7.767 51.323 44.075 1.00 35.58 1243 CB LYS 681 8.779 54.391 43.419 1.00 37.62 1244 CG LYS 651 9.834 55.481 43.433 1.00 43.12 1245 CD LYS 681 9.273 56.849 43.827 1.00 55.06 1246 CE LYS 681 10.419 57.868 43.884 1.00 99.90 1247 NZ LYS 681 9.864 59.218 44.093 1.00 99.90 1248 N SER 682 7.734 51.854 41.880 1.00 28.39 1249 CA SER 682 6.667 50.925 41.537 1.00 29.00 1250 C SER 682 7.282 49.701 40.864 1.00 30.23 1251 O SER 682 6.865 49.312 39.778 1.00 26.81 1252 CB SER 682 5.678 51.594 40.578 1.00 23.84 1253 OG SER 682 4.977 52.693 41.139 1.00 31.90 1254 N GLN 683 8.273 49.089 41.508 1.00 29.41 1255 CA GLN 683 8.936 47.936 40.910 1.00 28.12 1256 C GLN 683 7.980 46.776 40.638 1.00 30.39 1257 O GLN 683 8.040 46.157 39.582 1.00 26.03 1258 CB GLN 683 10.088 47.471 41.801 1.00 25.64 1259 CG GLN 683 11.048 46.487 41.154 1.00 32.23 1260 CD GLN 683 11.776 47.082 39.957 1.00 37.10 1261 OE1 GLN 683 12.179 48.247 39.972 1.00 37.64 1262 NE2 GLN 683 12.010 46.204 38.875 1.00 42.95 1263 N GLU 684 7.107 46.462 41.592 1.00 27.88 1264 CA GLU 684 6.155 45.374 41.386 1.00 30.26 1265 C GLU 684 5.275 45.594 40.169 1.00 27.76 1266 O GLU 684 5.134 44.699 39.332 1.00 28.54 1267 CB GLU 684 5.237 45.203 42.590 1.00 31.84 1268 CG GLU 684 4.246 46.371 42.908 1.00 99.90 1269 CD GLU 684 3.384 46.270 44.169 1.00 99.90 1270 OE1 GLU 684 2.605 47.147 44.516 1.00 99.90 1271 OE2 GLU 684 3.567 45.114 44.867 1.00 99.90 1272 N LEU 685 4.674 46.779 40.087 1.00 27.40 1273 CA LEU 685 3.816 47.129 38.965 1.00 27.76 1274 C LEU 685 4.627 47.085 37.676 1.00 27.08 1275 O LEU 685 4.134 46.647 36.636 1.00 24.43 1276 CB LEU 685 3.232 48.527 39.136 1.00 29.57 1277 CG LEU 685 2.395 48.818 40.411 1.00 99.90 1278 CD1 LEU 685 1.806 50.235 40.343 1.00 99.90 1279 CD2 LEU 685 1.265 47.798 40.626 1.00 99.90 1280 N PHE 686 5.875 47.527 37.758 1.00 25.08 1281 CA PHE 686 6.751 47.536 36.586 1.00 25.20 1282 C PHE 686 7.026 46.127 36.084 1.00 22.17 1283 O PHE 686 6.972 45.868 34.879 1.00 24.69 1284 CB PHE 686 8.060 48.268 36.910 1.00 24.39 1285 CG PHE 686 9.148 48.066 35.883 1.00 25.18 1286 CD1 PHE 686 9.213 48.875 34.740 1.00 26.95 1287 CD2 PHE 686 10.079 47.041 36.029 1.00 21.90 1288 CE1 PHE 686 10.198 48.660 33.756 1.00 22.61 1289 CE2 PHE 686 11.065 46.812 35.054 1.00 21.56 1290 CZ PHE 686 11.124 47.622 33.915 1.00 23.75 1291 N ASP 687 7.312 45.216 37.004 1.00 26.80 1292 CA ASP 687 7.573 43.819 36.640 1.00 30.80 1293 C ASP 687 6.365 43.212 35.929 1.00 27.28 1294 O ASP 687 6.498 42.543 34.905 1.00 27.77 1295 CB ASP 687 7.859 42.979 37.890 1.00 28.70 1296 CG ASP 687 8.326 41.535 37.658 1.00 99.90 1297 OD1 ASP 687 7.948 40.595 38.342 1.00 99.90 1298 OD2 ASP 687 9.181 41.418 36.599 1.00 99.90 1299 N GLU 688 5.188 43.418 36.505 1.00 29.50 1300 CA GLU 688 3.961 42.897 35.922 1.00 27.52 1301 C GLU 688 3.731 43.493 34.533 1.00 29.29 1302 O GLU 688 3.318 42.805 33.610 1.00 29.26 1303 CB GLU 688 2.762 43.210 36.826 1.00 32.59 1304 CG GLU 688 2.653 42.336 38.078 1.00 38.26 1305 CD GLU 688 1.528 42.774 39.012 1.00 47.34 1306 OE1 GLU 688 0.440 43.140 38.517 1.00 51.54 1307 OE2 GLU 688 1.720 42.734 40.248 1.00 49.88 1308 N ILE 689 4.007 44.777 34.381 1.00 25.95 1309 CA ILE 689 3.803 45.408 33.093 1.00 26.70 1310 C ILE 689 4.737 44.798 32.059 1.00 26.41 1311 O ILE 689 4.317 44.414 30.966 1.00 25.61 1312 CB ILE 689 4.044 46.907 33.209 1.00 26.67 1313 CG2 ILE 689 3.757 47.671 31.880 1.00 99.90 1314 CG1 ILE 689 3.246 47.608 34.354 1.00 99.90 1315 CD1 ILE 689 3.697 49.040 34.711 1.00 99.90 1316 N ARG 690 6.007 44.684 32.422 1.00 26.84 1317 CA ARG 690 6.989 44.124 31.515 1.00 29.65 1318 C ARG 690 6.600 42.691 31.106 1.00 31.46 1319 O ARG 690 6.645 42.341 29.931 1.00 28.49 1320 CB ARG 690 8.366 44.185 32.177 1.00 29.38 1321 CG ARG 690 9.522 43.957 31.232 1.00 38.40 1322 CD ARG 690 10.844 44.337 31.875 1.00 33.58 1323 NE ARG 690 11.947 44.131 30.940 1.00 43.23 1324 CZ ARG 690 12.434 42.942 30.613 1.00 45.03 1325 NH1 ARG 690 12.020 41.789 31.215 1.00 58.21 1326 NH2 ARG 690 13.427 42.875 29.683 1.00 52.78 1327 N MET 691 6.189 41.870 32.066 1.00 29.00 1328 CA MET 691 5.783 40.497 31.758 1.00 29.23 1329 C MET 691 4.586 40.447 30.814 1.00 25.05 1330 O MET 691 4.523 39.601 29.929 1.00 27.74 1331 CB MET 691 5.456 39.741 33.047 1.00 29.17 1332 CG MET 691 6.626 39.562 34.038 1.00 99.90 1333 SD MET 691 6.151 38.415 35.341 1.00 99.90 1334 CE MET 691 7.506 38.731 36.480 1.00 99.90 1335 N THR 692 3.631 41.346 31.015 1.00 27.46 1336 CA THR 692 2.445 41.405 30.170 1.00 26.94 1337 C THR 692 2.837 41.701 28.727 1.00 28.69 1338 O THR 692 2.275 41.136 27.797 1.00 24.01 1339 CB THR 692 1.488 42.485 30.676 1.00 33.23 1340 OG1 THR 692 1.053 42.187 31.996 1.00 99.90 1341 CG2 THR 692 0.183 42.674 29.872 1.00 99.90 1342 N TYR 693 3.799 42.594 28.538 1.00 23.69 1343 CA TYR 693 4.232 42.918 27.185 1.00 24.43 1344 C TYR 693 5.124 41.845 26.579 1.00 25.10 1345 O TYR 693 5.160 41.684 25.364 1.00 24.91 1346 CB TYR 693 4.888 44.291 27.176 1.00 22.98 1347 CG TYR 693 3.840 45.374 27.203 1.00 21.21 1348 CD1 TYR 693 3.165 45.732 26.032 1.00 21.26 1349 CD2 TYR 693 3.489 46.007 28.393 1.00 21.12 1350 CE1 TYR 693 2.165 46.700 26.038 1.00 22.44 1351 CE2 TYR 693 2.487 46.979 28.411 1.00 23.86 1352 CZ TYR 693 1.829 47.325 27.225 1.00 28.65 1353 OH TYR 693 0.884 48.311 27.226 1.00 23.47 1354 N ILE 694 5.835 41.101 27.415 1.00 23.21 1355 CA ILE 694 6.650 40.015 26.901 1.00 29.14 1356 C ILE 694 5.653 38.965 26.405 1.00 30.21 1357 O ILE 694 5.832 38.363 25.350 1.00 26.87 1358 CB ILE 694 7.584 39.430 28.003 1.00 29.35 1359 CG1 ILE 694 8.690 40.443 28.327 1.00 23.92 1360 CG2 ILE 694 8.219 38.114 27.542 1.00 27.00 1361 CD1 ILE 694 9.626 39.992 29.412 1.00 22.76 1362 N LYS 695 4.577 38.764 27.154 1.00 28.71 1363 CA LYS 695 3.580 37.801 26.724 1.00 32.10 1364 C LYS 695 2.890 38.286 25.458 1.00 29.94 1365 O LYS 695 2.487 37.489 24.621 1.00 28.11 1366 CB LYS 695 2.522 37.554 27.805 1.00 35.86 1367 CG LYS 695 3.015 36.798 29.026 1.00 40.68 1368 CD LYS 695 1.838 36.332 29.882 1.00 46.12 1369 CE LYS 695 2.368 35.511 31.065 1.00 99.90 1370 NZ LYS 695 1.257 35.206 31.985 1.00 99.90 1371 N GLU 696 2.754 39.596 25.307 1.00 26.26 1372 CA GLU 696 2.094 40.106 24.118 1.00 24.07 1373 C GLU 696 2.995 39.939 22.890 1.00 25.19 1374 O GLU 696 2.502 39.675 21.789 1.00 27.72 1375 CB GLU 696 1.691 41.569 24.316 1.00 29.75 1376 CG GLU 696 0.566 42.010 23.401 1.00 32.34 1377 CD GLU 696 −0.741 41.254 23.669 1.00 48.72 1378 OE1 GLU 696 −0.808 40.500 24.667 1.00 47.00 1379 OE2 GLU 696 −1.707 41.419 22.889 1.00 46.97 1380 N LEU 697 4.306 40.085 23.073 1.00 23.97 1381 CA LEU 697 5.250 39.893 21.974 1.00 22.66 1382 C LEU 697 5.147 38.432 21.518 1.00 30.81 1383 O LEU 697 5.247 38.138 20.329 1.00 24.16 1384 CB LEU 697 6.684 40.158 22.448 1.00 22.80 1385 CG LEU 697 7.794 39.746 21.476 1.00 25.24 1386 CD1 LEU 697 7.669 40.557 20.215 1.00 25.51 1387 CD2 LEU 697 9.177 39.940 22.125 1.00 27.39 1388 N GLY 698 4.980 37.516 22.471 1.00 24.04 1389 CA GLY 698 4.860 36.103 22.122 1.00 29.31 1390 C GLY 698 3.637 35.900 21.243 1.00 28.39 1391 O GLY 698 3.714 35.207 20.229 1.00 28.22 1392 N LYS 699 2.519 36.528 21.607 1.00 29.91 1393 CA LYS 699 1.296 36.425 20.808 1.00 27.78 1394 C LYS 699 1.524 37.002 19.413 1.00 28.75 1395 O LYS 699 1.047 36.459 18.420 1.00 30.96 1396 CB LYS 699 0.141 37.175 21.469 1.00 32.36 1397 CG LYS 699 −0.319 36.605 22.790 1.00 32.65 1398 CD LYS 699 −1.435 37.474 23.360 1.00 41.08 1399 CE LYS 699 −1.870 36.970 24.710 1.00 47.72 1400 NZ LYS 699 −0.742 36.892 25.724 1.00 54.97 1401 N ALA 700 2.254 38.111 19.334 1.00 25.66 1402 CA ALA 700 2.515 38.726 18.035 1.00 26.89 1403 C ALA 700 3.302 37.744 17.175 1.00 25.18 1404 O ALA 700 3.029 37.591 15.981 1.00 24.74 1405 CB ALA 700 3.305 40.026 18.206 1.00 22.45 1406 N ILE 701 4.271 37.081 17.794 1.00 25.69 1407 CA ILE 701 5.112 36.113 17.088 1.00 28.42 1408 C ILE 701 4.237 34.945 16.627 1.00 32.00 1409 O ILE 701 4.394 34.448 15.513 1.00 33.59 1410 CB ILE 701 6.243 35.612 18.008 1.00 31.03 1411 CG1 ILE 701 7.259 36.743 18.217 1.00 25.53 1412 CG2 ILE 701 6.912 34.369 17.417 1.00 29.18 1413 CD1 ILE 701 8.342 36.413 19.218 1.00 27.39 1414 N VAL 702 3.311 34.534 17.488 1.00 33.82 1415 CA VAL 702 2.409 33.440 17.168 1.00 34.58 1416 C VAL 702 1.484 33.695 15.991 1.00 37.55 1417 O VAL 702 0.987 32.754 15.368 1.00 37.64 1418 CB VAL 702 1.584 33.033 18.453 1.00 99.90 1419 CG1 VAL 702 2.450 32.451 19.597 1.00 99.90 1420 CG2 VAL 702 0.440 32.002 18.241 1.00 99.90 1421 N LYS 703 1.246 34.963 15.675 1.00 33.59 1422 CA LYS 703 0.379 35.312 14.563 1.00 37.87 1423 C LYS 703 0.909 34.783 13.231 1.00 42.05 1424 O LYS 703 0.137 34.548 12.304 1.00 37.32 1425 CB LYS 703 0.220 36.832 14.468 1.00 35.77 1426 CG LYS 703 −0.753 37.281 13.349 1.00 99.90 1427 CD LYS 703 −0.887 38.797 13.181 1.00 99.90 1428 CE LYS 703 −1.819 39.094 11.999 1.00 99.90 1429 NZ LYS 703 −2.088 40.542 11.940 1.00 99.90 1430 N ARG 704 2.223 34.592 13.144 1.00 42.57 1431 CA ARG 704 2.855 34.129 11.915 1.00 52.08 1432 C ARG 704 3.857 33.000 12.122 1.00 54.79 1433 O ARG 704 4.295 32.377 11.153 1.00 58.54 1434 CB ARG 704 3.553 35.300 11.220 1.00 52.12 1435 CG ARG 704 2.602 36.399 10.773 1.00 58.32 1436 CD ARG 704 3.330 37.570 10.125 1.00 61.04 1437 NE ARG 704 2.381 38.552 9.608 1.00 72.95 1438 CZ ARG 704 2.717 39.679 8.985 1.00 76.45 1439 NH1 ARG 704 4.016 40.006 8.710 1.00 80.87 1440 NH2 ARG 704 1.724 40.535 8.609 1.00 77.97 1441 N GLU 705 4.232 32.744 13.373 1.00 60.36 1442 CA GLU 705 5.173 31.670 13.672 1.00 65.05 1443 C GLU 705 4.462 30.478 14.296 1.00 67.98 1444 O GLU 705 4.360 30.349 15.520 1.00 68.79 1445 CB GLU 705 6.299 32.164 14.581 1.00 64.71 1446 CG GLU 705 7.176 33.211 13.919 1.00 68.26 1447 CD GLU 705 7.851 32.703 12.655 1.00 71.18 1448 OE1 GLU 705 8.482 33.467 11.921 1.00 72.78 1449 OE2 GLU 705 7.975 31.348 12.607 1.00 99.90 1450 N GLY 706 3.967 29.621 13.410 1.00 70.37 1451 CA GLY 706 3.248 28.405 13.752 1.00 71.87 1452 C GLY 706 4.084 27.416 14.573 1.00 72.34 1453 O GLY 706 3.661 26.978 15.646 1.00 71.39 1454 N ASN 707 5.266 27.069 14.068 1.00 72.03 1455 CA ASN 707 6.127 26.131 14.769 1.00 72.71 1456 C ASN 707 6.392 26.503 16.219 1.00 71.15 1457 O ASN 707 6.651 27.665 16.528 1.00 71.21 1458 CB ASN 707 7.464 25.970 13.989 1.00 99.90 1459 CG ASN 707 7.366 25.516 12.528 1.00 99.90 1460 OD1 ASN 707 7.454 26.300 11.595 1.00 99.90 1461 ND2 ASN 707 7.157 24.252 12.275 1.00 99.90 1462 N SER 708 6.330 25.521 17.110 1.00 70.79 1463 CA SER 708 6.571 25.759 18.531 1.00 69.40 1464 C SER 708 8.038 26.104 18.772 1.00 68.93 1465 O SER 708 8.369 26.841 19.706 1.00 66.12 1466 CB SER 708 6.215 24.515 19.380 1.00 71.43 1467 OG SER 708 7.120 23.424 19.176 1.00 99.90 1468 N SER 709 8.912 25.561 17.929 1.00 65.17 1469 CA SER 709 10.339 25.819 18.054 1.00 64.59 1470 C SER 709 10.702 27.013 17.180 1.00 61.44 1471 O SER 709 11.567 27.811 17.531 1.00 61.24 1472 CB SER 709 11.177 24.591 17.623 1.00 65.52 1473 OG SER 709 11.115 24.341 16.214 1.00 99.90 1474 N GLN 710 10.031 27.128 16.038 1.00 58.29 1475 CA GLN 710 10.272 28.237 15.129 1.00 52.84 1476 C GLN 710 9.868 29.527 15.841 1.00 51.66 1477 O GLN 710 10.538 30.553 15.720 1.00 45.86 1478 CB GLN 710 9.447 28.068 13.852 1.00 55.37 1479 CG GLN 710 9.639 29.168 12.755 1.00 99.90 1480 CD GLN 710 8.801 29.099 11.472 1.00 99.90 1481 OE1 GLN 710 8.894 29.959 10.612 1.00 99.90 1482 NE2 GLN 710 7.952 28.118 11.299 1.00 99.90 1483 N ASN 711 8.771 29.458 16.586 1.00 44.60 1484 CA ASN 711 8.278 30.608 17.328 1.00 45.64 1485 C ASN 711 9.227 30.873 18.485 1.00 44.47 1486 O ASN 711 9.455 32.018 18.873 1.00 39.29 1487 CB ASN 711 6.881 30.328 17.879 1.00 45.32 1488 CG ASN 711 5.799 29.942 16.865 1.00 99.90 1489 OD1 ASN 711 5.455 28.783 16.688 1.00 99.90 1490 ND2 ASN 711 5.242 30.883 16.151 1.00 99.90 1491 N TRP 712 9.779 29.796 19.029 1.00 43.23 1492 CA TRP 712 10.708 29.884 20.141 1.00 42.20 1493 C TRP 712 12.007 30.512 19.655 1.00 41.29 1494 O TRP 712 12.572 31.386 20.314 1.00 42.13 1495 CB TRP 712 10.974 28.488 20.708 1.00 43.71 1496 CG TRP 712 9.763 27.820 21.365 1.00 99.90 1497 CD1 TRP 712 8.899 26.892 20.747 1.00 99.90 1498 CD2 TRP 712 9.234 28.052 22.618 1.00 99.90 1499 NE1 TRP 712 7.834 26.530 21.595 1.00 99.90 1500 CE2 TRP 712 8.064 27.263 22.748 1.00 99.90 1501 CE3 TRP 712 9.649 28.908 23.670 1.00 99.90 1502 CZ2 TRP 712 7.306 27.317 23.938 1.00 99.90 1503 CZ3 TRP 712 8.887 28.939 24.838 1.00 99.90 1504 CH2 TRP 712 7.733 28.153 24.972 1.00 99.90 1505 N GLN 713 12.482 30.063 18.497 1.00 35.72 1506 CA GLN 713 13.705 30.607 17.932 1.00 36.75 1507 C GLN 713 13.471 32.064 17.536 1.00 31.61 1508 O GLN 713 14.390 32.882 17.555 1.00 34.73 1509 CB GLN 713 14.140 29.779 16.718 1.00 41.06 1510 CG GLN 713 14.425 28.316 17.080 1.00 51.40 1511 CD GLN 713 14.813 27.460 15.891 1.00 56.24 1512 OE1 GLN 713 15.833 27.698 15.240 1.00 66.21 1513 NE2 GLN 713 13.872 26.543 15.379 1.00 61.83 1514 N ARG 714 12.228 32.377 17.194 1.00 30.91 1515 CA ARG 714 11.838 33.731 16.791 1.00 33.76 1516 C ARG 714 11.909 34.647 18.007 1.00 29.74 1517 O ARG 714 12.398 35.776 17.934 1.00 28.46 1518 CB ARG 714 10.410 33.710 16.264 1.00 31.23 1519 CG ARG 714 9.875 35.044 15.774 1.00 40.84 1520 CD ARG 714 10.660 35.529 14.587 1.00 36.78 1521 NE ARG 714 10.044 36.692 13.951 1.00 41.13 1522 CZ ARG 714 10.522 37.255 12.851 1.00 35.24 1523 NH1 ARG 714 11.641 36.755 12.245 1.00 32.73 1524 NH2 ARG 714 9.876 38.307 12.292 1.00 33.12 1525 N PHE 715 11.410 34.140 19.125 1.00 27.87 1526 CA PHE 715 11.411 34.896 20.360 1.00 29.28 1527 C PHE 715 12.853 35.180 20.724 1.00 30.03 1528 O PHE 715 13.198 36.292 21.131 1.00 29.75 1529 CB PHE 715 10.742 34.102 21.471 1.00 30.24 1530 CG PHE 715 10.605 34.864 22.757 1.00 32.22 1531 CD1 PHE 715 9.640 35.859 22.893 1.00 30.59 1532 CD2 PHE 715 11.446 34.593 23.829 1.00 33.43 1533 CE1 PHE 715 9.515 36.573 24.083 1.00 29.82 1534 CE2 PHE 715 11.330 35.300 25.020 1.00 33.14 1535 CZ PHE 715 10.360 36.294 25.147 1.00 28.67 1536 N TYR 716 13.709 34.180 20.544 1.00 28.46 1537 CA TYR 716 15.123 34.343 20.860 1.00 33.75 1538 C TYR 716 15.764 35.435 20.016 1.00 30.34 1539 O TYR 716 16.500 36.271 20.534 1.00 31.44 1540 CB TYR 716 15.905 33.043 20.630 1.00 32.68 1541 CG TYR 716 17.391 33.207 20.872 1.00 39.92 1542 CD1 TYR 716 17.904 33.299 22.163 1.00 45.08 1543 CD2 TYR 716 18.278 33.335 19.805 1.00 45.67 1544 CE1 TYR 716 19.270 33.517 22.389 1.00 52.13 1545 CE2 TYR 716 19.643 33.556 20.017 1.00 51.47 1546 CZ TYR 716 20.131 33.646 21.308 1.00 51.04 1547 OH TYR 716 21.474 33.869 21.525 1.00 54.66 1548 N GLN 717 15.487 35.410 18.717 1.00 27.62 1549 CA GLN 717 16.038 36.383 17.792 1.00 28.60 1550 C GLN 717 15.598 37.812 18.104 1.00 30.83 1551 O GLN 717 16.418 38.742 18.128 1.00 26.66 1552 CB GLN 717 15.619 36.045 16.365 1.00 34.35 1553 CG GLN 717 16.070 34.670 15.891 1.00 38.32 1554 CD GLN 717 15.625 34.389 14.474 1.00 43.83 1555 OE1 GLN 717 14.434 34.436 14.160 1.00 44.13 1556 NE2 GLN 717 16.629 34.027 13.543 1.00 49.31 1557 N LEU 718 14.303 37.983 18.334 1.00 26.84 1558 CA LEU 718 13.774 39.309 18.625 1.00 25.39 1559 C LEU 718 14.288 39.865 19.949 1.00 27.79 1560 O LEU 718 14.634 41.050 20.032 1.00 27.31 1561 CB LEU 718 12.242 39.283 18.616 1.00 24.65 1562 CG LEU 718 11.635 38.865 17.267 1.00 26.51 1563 CD1 LEU 718 10.131 38.939 17.303 1.00 29.15 1564 CD2 LEU 718 12.187 39.757 16.171 1.00 24.41 1565 N THR 719 14.346 39.025 20.979 1.00 26.19 1566 CA THR 719 14.824 39.484 22.274 1.00 29.70 1567 C THR 719 16.339 39.696 22.245 1.00 32.67 1568 O THR 719 16.878 40.522 22.992 1.00 30.17 1569 CB THR 719 14.411 38.513 23.424 1.00 29.72 1570 OG1 THR 719 14.908 37.198 23.251 1.00 33.15 1571 CG2 THR 719 12.906 38.435 23.520 1.00 32.70 1572 N LYS 720 17.037 38.976 21.374 1.00 29.23 1573 CA LYS 720 18.481 39.162 21.281 1.00 29.94 1574 C LYS 720 18.709 40.525 20.625 1.00 25.15 1575 O LYS 720 19.630 41.242 20.971 1.00 30.87 1576 CB LYS 720 19.122 38.049 20.435 1.00 32.66 1577 CG LYS 720 20.649 38.024 20.484 1.00 41.23 1578 CD LYS 720 21.154 37.764 21.902 1.00 45.10 1579 CE LYS 720 22.671 37.785 21.969 1.00 45.88 1580 NZ LYS 720 23.231 37.484 23.350 1.00 50.22 1581 N LEU 721 17.849 40.890 19.682 1.00 28.84 1582 CA LEU 721 17.962 42.186 19.014 1.00 30.79 1583 C LEU 721 17.799 43.313 20.049 1.00 31.46 1584 O LEU 721 18.563 44.282 20.056 1.00 28.53 1585 CB LEU 721 16.910 42.303 17.913 1.00 29.92 1586 CG LEU 721 16.843 43.583 17.069 1.00 36.08 1587 CD1 LEU 721 16.109 43.302 15.767 1.00 37.87 1588 CD2 LEU 721 16.139 44.675 17.848 1.00 34.23 1589 N LEU 722 16.813 43.179 20.930 1.00 26.83 1590 CA LEU 722 16.603 44.188 21.966 1.00 32.06 1591 C LEU 722 17.838 44.293 22.860 1.00 31.54 1592 O LEU 722 18.268 45.405 23.208 1.00 27.43 1593 CB LEU 722 15.368 43.847 22.804 1.00 28.40 1594 CG LEU 722 14.020 43.968 22.085 1.00 33.60 1595 CD1 LEU 722 12.898 43.593 23.039 1.00 27.76 1596 CD2 LEU 722 13.817 45.402 21.578 1.00 36.94 1597 N ASP 723 18.404 43.144 23.242 1.00 30.89 1598 CA ASP 723 19.615 43.141 24.069 1.00 31.45 1599 C ASP 723 20.725 43.895 23.355 1.00 33.06 1600 O ASP 723 21.418 44.710 23.967 1.00 27.21 1601 CB ASP 723 20.131 41.719 24.340 1.00 32.85 1602 CG ASP 723 19.307 40.964 25.374 1.00 41.09 1603 OD1 ASP 723 18.366 41.546 25.954 1.00 34.77 1604 OD2 ASP 723 19.617 39.770 25.609 1.00 35.56 1605 N SER 724 20.909 43.607 22.066 1.00 23.23 1606 CA SER 724 21.960 44.274 21.307 1.00 29.88 1607 C SER 724 21.770 45.780 21.172 1.00 27.44 1608 O SER 724 22.735 46.513 20.960 1.00 28.18 1609 CB SER 724 22.114 43.636 19.917 1.00 30.74 1610 OG SER 724 20.999 43.898 19.058 1.00 99.90 1611 N MET 725 20.537 46.251 21.314 1.00 27.04 1612 CA MET 725 20.295 47.688 21.211 1.00 28.38 1613 C MET 725 21.054 48.489 22.279 1.00 29.38 1614 O MET 725 21.465 49.630 22.043 1.00 26.74 1615 CB MET 725 18.795 47.975 21.288 1.00 27.75 1616 CG MET 725 17.936 47.376 20.154 1.00 99.90 1617 SD MET 725 16.267 48.046 20.234 1.00 99.90 1618 CE MET 725 15.466 46.902 19.103 1.00 99.90 1619 N HIS 726 21.256 47.893 23.446 1.00 25.82 1620 CA HIS 726 21.974 48.580 24.517 1.00 26.55 1621 C HIS 726 23.345 49.086 24.078 1.00 28.01 1622 O HIS 726 23.671 50.249 24.293 1.00 26.18 1623 CB HIS 726 22.127 47.669 25.745 1.00 27.98 1624 CG HIS 726 20.895 47.574 26.592 1.00 31.07 1625 ND1 HIS 726 20.272 46.376 26.875 1.00 34.25 1626 CD2 HIS 726 20.192 48.527 27.252 1.00 25.45 1627 CE1 HIS 726 19.242 46.596 27.675 1.00 30.14 1628 NE2 HIS 726 19.172 47.892 27.917 1.00 32.22 1629 N GLU 727 24.148 48.238 23.446 1.00 30.88 1630 CA GLU 727 25.476 48.678 23.017 1.00 33.37 1631 C GLU 727 25.357 49.683 21.881 1.00 32.18 1632 O GLU 727 26.127 50.639 21.806 1.00 28.61 1633 CB GLU 727 26.327 47.486 22.573 1.00 41.89 1634 CG GLU 727 25.866 46.713 21.294 1.00 99.90 1635 CD GLU 727 26.640 45.457 20.886 1.00 99.90 1636 OE1 GLU 727 26.334 44.770 19.921 1.00 99.90 1637 OE2 GLU 727 27.699 45.178 21.696 1.00 99.90 1638 N VAL 728 24.394 49.464 20.991 1.00 25.95 1639 CA VAL 728 24.183 50.377 19.877 1.00 24.45 1640 C VAL 728 23.817 51.777 20.382 1.00 24.31 1641 O VAL 728 24.412 52.774 19.976 1.00 24.16 1642 CB VAL 728 23.092 49.899 18.861 1.00 25.35 1643 CG1 VAL 728 23.492 48.583 18.149 1.00 99.90 1644 CG2 VAL 728 22.782 50.963 17.778 1.00 99.90 1645 N VAL 729 22.824 51.844 21.261 1.00 23.01 1646 CA VAL 729 22.372 53.122 21.809 1.00 25.27 1647 C VAL 729 23.466 53.875 22.575 1.00 22.87 1648 O VAL 729 23.488 55.112 22.602 1.00 21.03 1649 CB VAL 729 21.152 52.905 22.732 1.00 28.67 1650 CG1 VAL 729 20.798 54.197 23.450 1.00 30.03 1651 CG2 VAL 729 19.961 52.435 21.898 1.00 28.50 1652 N GLU 730 24.366 53.132 23.200 1.00 23.37 1653 CA GLU 730 25.459 53.754 23.940 1.00 23.75 1654 C GLU 730 26.319 54.639 23.036 1.00 24.31 1655 O GLU 730 26.805 55.687 23.470 1.00 23.94 1656 CB GLU 730 26.325 52.689 24.594 1.00 23.23 1657 CG GLU 730 27.399 53.266 25.500 1.00 34.73 1658 CD GLU 730 28.403 52.304 26.141 1.00 99.90 1659 OE1 GLU 730 29.321 52.680 26.858 1.00 99.90 1660 OE2 GLU 730 28.179 50.996 25.838 1.00 99.90 1661 N ASN 731 26.510 54.228 21.781 1.00 20.06 1662 CA ASN 731 27.297 55.035 20.851 1.00 21.61 1663 C ASN 731 26.511 56.290 20.509 1.00 20.55 1664 O ASN 731 27.091 57.365 20.358 1.00 21.72 1665 CB ASN 731 27.630 54.313 19.522 1.00 27.13 1666 CG ASN 731 28.313 55.276 18.531 1.00 99.90 1667 OD1 ASN 731 27.690 55.787 17.614 1.00 99.90 1668 ND2 ASN 731 29.693 55.513 18.747 1.00 99.90 1669 N LEU 732 25.195 56.156 20.355 1.00 18.60 1670 CA LEU 732 24.372 57.322 20.073 1.00 19.89 1671 C LEU 732 24.400 58.268 21.297 1.00 21.61 1672 O LEU 732 24.496 59.486 21.145 1.00 18.84 1673 CB LEU 732 22.936 56.899 19.764 1.00 24.80 1674 CG LEU 732 22.703 55.942 18.590 1.00 32.83 1675 CD1 LEU 732 21.193 55.824 18.366 1.00 30.42 1676 CD2 LEU 732 23.369 56.464 17.329 1.00 34.48 1677 N LEU 733 24.312 57.712 22.508 1.00 20.58 1678 CA LEU 733 24.351 58.531 23.734 1.00 19.88 1679 C LEU 733 25.661 59.317 23.841 1.00 23.80 1680 O LEU 733 25.669 60.503 24.181 1.00 21.80 1681 CB LEU 733 24.253 57.782 25.098 1.00 21.04 1682 CG LEU 733 23.046 56.856 25.403 1.00 99.90 1683 CD1 LEU 733 22.981 56.535 26.912 1.00 99.90 1684 CD2 LEU 733 21.687 57.385 24.900 1.00 99.90 1685 N ASN 734 26.774 58.653 23.543 1.00 22.67 1686 CA ASN 734 28.066 59.318 23.616 1.00 21.83 1687 C ASN 734 28.188 60.431 22.575 1.00 21.54 1688 O ASN 734 28.645 61.526 22.886 1.00 20.75 1689 CB ASN 734 29.250 58.341 23.367 1.00 20.66 1690 CG ASN 734 29.379 57.211 24.413 1.00 99.90 1691 OD1 ASN 734 28.890 57.286 25.529 1.00 99.90 1692 ND2 ASN 734 30.142 56.095 23.981 1.00 99.90 1693 N TYR 735 27.768 60.157 21.341 1.00 19.92 1694 CA TYR 735 27.850 61.170 20.282 1.00 19.47 1695 C TYR 735 26.977 62.389 20.650 1.00 22.05 1696 O TYR 735 27.375 63.553 20.494 1.00 20.67 1697 CB TYR 735 27.396 60.546 18.948 1.00 19.20 1698 CG TYR 735 27.693 61.397 17.736 1.00 27.69 1699 CD1 TYR 735 26.945 62.546 17.461 1.00 26.53 1700 CD2 TYR 735 28.743 61.070 16.878 1.00 24.52 1701 CE1 TYR 735 27.237 63.347 16.359 1.00 30.01 1702 CE2 TYR 735 29.043 61.863 15.778 1.00 26.75 1703 CZ TYR 735 28.285 62.998 15.525 1.00 33.34 1704 OH TYR 735 28.416 63.738 14.398 1.00 39.29 1705 N CYS 736 25.785 62.119 21.164 1.00 19.66 1706 CA CYS 736 24.859 63.176 21.560 1.00 21.68 1707 C CYS 736 25.421 64.067 22.674 1.00 20.24 1708 O CYS 736 25.420 65.295 22.574 1.00 22.45 1709 CB CYS 736 23.541 62.546 22.022 1.00 22.87 1710 SG CYS 736 22.282 63.748 22.564 1.00 25.25 1711 N PHE 737 25.901 63.448 23.738 1.00 21.55 1712 CA PHE 737 26.445 64.208 24.862 1.00 24.47 1713 C PHE 737 27.666 65.021 24.442 1.00 25.40 1714 O PHE 737 27.856 66.143 24.922 1.00 28.02 1715 CB PHE 737 26.898 63.269 26.010 1.00 24.44 1716 CG PHE 737 27.315 64.017 27.260 1.00 99.90 1717 CD1 PHE 737 26.499 65.065 27.832 1.00 99.90 1718 CD2 PHE 737 28.542 63.654 27.928 1.00 99.90 1719 CE1 PHE 737 26.921 65.758 29.018 1.00 99.90 1720 CE2 PHE 737 28.954 64.332 29.127 1.00 99.90 1721 CZ PHE 737 28.149 65.393 29.667 1.00 99.90 1722 N GLN 738 28.497 64.463 23.562 1.00 23.21 1723 CA GLN 738 29.658 65.202 23.063 1.00 23.92 1724 C GLN 738 29.226 66.424 22.255 1.00 25.99 1725 O GLN 738 29.753 67.514 22.440 1.00 27.51 1726 CB GLN 738 30.559 64.293 22.179 1.00 27.01 1727 CG GLN 738 31.843 64.932 21.588 1.00 99.90 1728 CD GLN 738 31.591 65.903 20.416 1.00 99.90 1729 OE1 GLN 738 31.978 67.059 20.459 1.00 99.90 1730 NE2 GLN 738 30.947 65.358 19.278 1.00 99.90 1731 N THR 739 28.287 66.230 21.337 1.00 25.80 1732 CA THR 739 27.800 67.322 20.501 1.00 25.04 1733 C THR 739 27.089 68.377 21.331 1.00 24.51 1734 O THR 739 27.152 69.566 21.020 1.00 28.41 1735 CB THR 739 26.837 66.791 19.405 1.00 22.97 1736 OG1 THR 739 27.460 65.817 18.573 1.00 23.34 1737 CG2 THR 739 26.356 67.912 18.511 1.00 25.92 1738 N PHE 740 26.423 67.928 22.391 1.00 23.12 1739 CA PHE 740 25.684 68.804 23.294 1.00 23.28 1740 C PHE 740 26.683 69.700 24.034 1.00 26.81 1741 O PHE 740 26.466 70.902 24.160 1.00 27.75 1742 CB PHE 740 24.899 67.961 24.302 1.00 22.97 1743 CG PHE 740 24.055 68.765 25.255 1.00 20.82 1744 CD1 PHE 740 22.905 69.411 24.823 1.00 21.56 1745 CD2 PHE 740 24.442 68.901 26.584 1.00 25.72 1746 CE1 PHE 740 22.143 70.187 25.698 1.00 26.99 1747 CE2 PHE 740 23.690 69.673 27.468 1.00 28.83 1748 CZ PHE 740 22.537 70.318 27.025 1.00 24.76 1749 N LEU 741 27.770 69.110 24.527 1.00 26.30 1750 CA LEU 741 28.799 69.887 25.225 1.00 27.51 1751 C LEU 741 29.519 70.858 24.274 1.00 30.83 1752 O LEU 741 29.941 71.946 24.679 1.00 31.33 1753 CB LEU 741 29.908 69.003 25.855 1.00 30.94 1754 CG LEU 741 29.523 68.182 27.115 1.00 99.90 1755 CD1 LEU 741 30.665 67.202 27.464 1.00 99.90 1756 CD2 LEU 741 29.190 69.075 28.331 1.00 99.90 1757 N ASP 742 29.648 70.476 23.005 1.00 29.65 1758 CA ASP 742 30.336 71.327 22.034 1.00 30.69 1759 C ASP 742 29.348 72.084 21.156 1.00 33.21 1760 O ASP 742 29.743 72.682 20.152 1.00 36.42 1761 CB ASP 742 31.235 70.464 21.144 1.00 34.22 1762 CG ASP 742 32.171 71.209 20.181 1.00 99.90 1763 OD1 ASP 742 32.386 70.834 19.037 1.00 99.90 1764 OD2 ASP 742 32.709 72.339 20.732 1.00 99.90 1765 N LYS 743 27.834 74.903 21.015 1.00 37.58 1766 CA LYS 743 28.165 76.351 20.660 1.00 43.27 1767 C LYS 743 29.304 76.341 19.648 1.00 46.14 1768 O LYS 743 29.279 77.087 18.665 1.00 46.04 1769 CB LYS 743 28.506 77.255 21.851 1.00 45.98 1770 CG LYS 743 27.451 77.232 22.956 1.00 58.17 1771 CD LYS 743 26.030 77.472 22.426 1.00 63.03 1772 CE LYS 743 25.032 77.361 23.586 1.00 99.90 1773 NZ LYS 743 23.692 77.759 23.119 1.00 99.90 1774 N THR 744 30.284 75.470 19.863 1.00 43.89 1775 CA THR 744 31.426 75.374 18.965 1.00 44.86 1776 C THR 744 31.055 74.760 17.623 1.00 45.61 1777 O THR 744 31.589 75.140 16.583 1.00 44.57 1778 CB THR 744 32.532 74.549 19.617 1.00 49.14 1779 OG1 THR 744 32.980 75.173 20.814 1.00 99.90 1780 CG2 THR 744 33.816 74.345 18.784 1.00 99.90 1781 N MET 745 30.135 73.805 17.654 1.00 44.06 1782 CA MET 745 29.702 73.117 16.446 1.00 42.19 1783 C MET 745 28.543 73.819 15.762 1.00 40.67 1784 O MET 745 28.123 73.419 14.680 1.00 44.90 1785 CB MET 745 29.360 71.629 16.758 1.00 39.53 1786 CG MET 745 29.529 70.678 15.549 1.00 99.90 1787 SD MET 745 29.499 68.900 15.994 1.00 99.90 1788 CE MET 745 31.285 68.588 16.215 1.00 99.90 1789 N SER 746 28.044 74.878 16.387 1.00 38.21 1790 CA SER 746 26.919 75.618 15.851 1.00 35.93 1791 C SER 746 25.688 74.721 15.769 1.00 34.57 1792 O SER 746 24.879 74.855 14.856 1.00 33.32 1793 CB SER 746 27.243 76.177 14.458 1.00 42.40 1794 OG SER 746 28.273 77.165 14.476 1.00 50.36 1795 N ILE 747 25.548 73.805 16.726 1.00 32.92 1796 CA ILE 747 24.396 72.901 16.749 1.00 30.26 1797 C ILE 747 23.448 73.310 17.879 1.00 31.81 1798 O ILE 747 23.850 73.383 19.035 1.00 34.09 1799 CB ILE 747 24.818 71.410 16.872 1.00 30.61 1800 CG2 ILE 747 23.605 70.496 17.156 1.00 99.90 1801 CG1 ILE 747 25.526 70.975 15.562 1.00 99.90 1802 CD1 ILE 747 26.220 69.611 15.607 1.00 99.90 1803 N GLU 748 22.197 73.600 17.536 1.00 28.12 1804 CA GLU 748 21.214 73.984 18.537 1.00 27.45 1805 C GLU 748 20.405 72.802 19.068 1.00 27.94 1806 O GLU 748 19.952 71.973 18.288 1.00 26.23 1807 CB GLU 748 20.238 75.010 17.965 1.00 33.68 1808 CG GLU 748 19.118 75.361 18.944 1.00 51.81 1809 CD GLU 748 18.123 76.367 18.393 1.00 62.71 1810 OE1 GLU 748 18.298 76.824 17.240 1.00 63.38 1811 OE2 GLU 748 17.160 76.703 19.123 1.00 63.52 1812 N PHE 749 20.236 72.733 20.392 1.00 25.35 1813 CA PHE 749 19.440 71.681 21.029 1.00 24.39 1814 C PHE 749 18.254 72.387 21.663 1.00 26.69 1815 O PHE 749 18.441 73.352 22.404 1.00 27.33 1816 CB PHE 749 20.204 70.946 22.155 1.00 25.14 1817 CG PHE 749 21.267 69.994 21.674 1.00 21.63 1818 CD1 PHE 749 22.475 70.460 21.184 1.00 22.11 1819 CD2 PHE 749 21.036 68.626 21.691 1.00 23.38 1820 CE1 PHE 749 23.442 69.575 20.719 1.00 19.55 1821 CE2 PHE 749 21.992 67.725 21.228 1.00 24.14 1822 CZ PHE 749 23.200 68.201 20.740 1.00 22.83 1823 N PRO 750 17.022 71.932 21.382 1.00 23.73 1824 CA PRO 750 15.833 72.563 21.961 1.00 22.74 1825 C PRO 750 15.766 72.286 23.474 1.00 22.33 1826 O PRO 750 16.501 71.459 24.004 1.00 22.26 1827 CB PRO 750 14.683 71.901 21.198 1.00 24.51 1828 CG PRO 750 15.346 71.451 19.899 1.00 30.94 1829 CD PRO 750 16.607 70.851 20.478 1.00 29.32 1830 N GLU 751 14.861 72.976 24.153 1.00 25.11 1831 CA GLU 751 14.721 72.860 25.610 1.00 22.58 1832 C GLU 751 14.366 71.515 26.232 1.00 21.81 1833 O GLU 751 14.968 71.112 27.220 1.00 23.58 1834 CB GLU 751 13.704 73.894 26.097 1.00 23.00 1835 CG GLU 751 14.072 75.366 25.825 1.00 25.08 1836 CD GLU 751 15.381 75.828 26.459 1.00 31.26 1837 OE1 GLU 751 15.751 75.341 27.550 1.00 31.56 1838 OE2 GLU 751 16.034 76.725 25.879 1.00 31.17 1839 N MET 752 13.369 70.820 25.692 1.00 20.50 1840 CA MET 752 12.989 69.543 26.286 1.00 22.40 1841 C MET 752 14.077 68.499 26.093 1.00 20.88 1842 O MET 752 14.348 67.698 26.987 1.00 22.84 1843 CB MET 752 11.659 69.064 25.692 1.00 28.13 1844 CG MET 752 10.536 70.073 25.898 1.00 30.10 1845 SD MET 752 8.936 69.576 25.227 1.00 36.75 1846 CE MET 752 9.384 69.107 23.548 1.00 29.48 1847 N LEU 753 14.719 68.514 24.932 1.00 22.18 1848 CA LEU 753 15.778 67.555 24.665 1.00 20.40 1849 C LEU 753 16.986 67.882 25.514 1.00 20.24 1850 O LEU 753 17.662 66.988 26.013 1.00 20.23 1851 CB LEU 753 16.131 67.658 23.154 1.00 24.51 1852 CG LEU 753 17.165 66.660 22.591 1.00 99.90 1853 CD1 LEU 753 16.675 65.204 22.693 1.00 99.90 1854 CD2 LEU 753 17.507 66.994 21.122 1.00 99.90 1855 N ALA 754 17.262 69.171 25.680 1.00 22.17 1856 CA ALA 754 18.392 69.574 26.501 1.00 24.13 1857 C ALA 754 18.157 69.098 27.942 1.00 24.76 1858 O ALA 754 19.097 68.690 28.634 1.00 20.25 1859 CB ALA 754 18.553 71.102 26.477 1.00 24.96 1860 N GLU 755 16.907 69.162 28.393 1.00 21.90 1861 CA GLU 755 16.600 68.727 29.754 1.00 25.07 1862 C GLU 755 16.830 67.238 29.977 1.00 25.56 1863 O GLU 755 17.432 66.860 30.971 1.00 26.95 1864 CB GLU 755 15.163 69.086 30.153 1.00 26.93 1865 CG GLU 755 14.785 68.556 31.538 1.00 30.33 1866 CD GLU 755 15.673 69.098 32.663 1.00 45.68 1867 OE1 GLU 755 16.238 70.205 32.515 1.00 48.37 1868 OE2 GLU 755 15.790 68.424 33.714 1.00 40.75 1869 N ILE 756 16.358 66.385 29.072 1.00 23.66 1870 CA ILE 756 16.559 64.963 29.273 1.00 24.09 1871 C ILE 756 18.031 64.596 29.179 1.00 22.11 1872 O ILE 756 18.500 63.731 29.918 1.00 23.47 1873 CB ILE 756 15.714 64.091 28.272 1.00 25.40 1874 CG2 ILE 756 15.854 62.560 28.536 1.00 99.90 1875 CG1 ILE 756 14.191 64.439 28.230 1.00 99.90 1876 CD1 ILE 756 13.396 63.843 27.050 1.00 99.90 1877 N ILE 757 18.775 65.274 28.301 1.00 20.76 1878 CA ILE 757 20.201 64.977 28.158 1.00 20.13 1879 C ILE 757 20.932 65.313 29.441 1.00 23.37 1880 O ILE 757 21.695 64.500 29.980 1.00 25.36 1881 CB ILE 757 20.826 65.763 26.979 1.00 19.24 1882 CG1 ILE 757 20.290 65.215 25.661 1.00 22.39 1883 CG2 ILE 757 22.352 65.650 27.013 1.00 18.20 1884 CD1 ILE 757 20.522 66.153 24.469 1.00 26.26 1885 N THR 758 20.684 66.509 29.948 1.00 23.60 1886 CA THR 758 21.324 66.958 31.177 1.00 30.05 1887 C THR 758 20.880 66.163 32.401 1.00 27.97 1888 O THR 758 21.666 65.921 33.317 1.00 31.89 1889 CB THR 758 21.042 68.460 31.398 1.00 24.81 1890 OG1 THR 758 21.578 69.230 30.329 1.00 99.90 1891 CG2 THR 758 21.647 69.091 32.671 1.00 99.90 1892 N ASN 759 19.624 65.745 32.427 1.00 28.98 1893 CA ASN 759 19.128 65.006 33.580 1.00 30.10 1894 C ASN 759 19.657 63.578 33.713 1.00 29.70 1895 O ASN 759 19.837 63.092 34.828 1.00 30.09 1896 CB ASN 759 17.596 64.990 33.572 1.00 29.66 1897 CG ASN 759 16.888 66.349 33.553 1.00 99.90 1898 OD1 ASN 759 16.425 66.829 32.529 1.00 99.90 1899 ND2 ASN 759 16.796 67.026 34.666 1.00 99.90 1900 N GLN 760 19.935 62.906 32.599 1.00 26.34 1901 CA GLN 760 20.377 61.526 32.700 1.00 23.29 1902 C GLN 760 21.537 61.004 31.859 1.00 23.47 1903 O GLN 760 22.127 59.991 32.231 1.00 24.44 1904 CB GLN 760 19.199 60.581 32.419 1.00 29.83 1905 CG GLN 760 17.964 60.724 33.272 1.00 31.14 1906 CD GLN 760 18.228 60.589 34.752 1.00 37.37 1907 OE1 GLN 760 19.070 59.800 35.180 1.00 33.07 1908 NE2 GLN 760 17.354 61.340 35.577 1.00 42.40 1909 N ILE 761 21.852 61.619 30.719 1.00 24.92 1910 CA ILE 761 22.919 61.043 29.888 1.00 27.91 1911 C ILE 761 24.248 60.745 30.555 1.00 27.51 1912 O ILE 761 24.799 59.664 30.369 1.00 30.01 1913 CB ILE 761 23.140 61.825 28.556 1.00 28.45 1914 CG2 ILE 761 24.335 61.277 27.746 1.00 99.90 1915 CG1 ILE 761 21.864 61.785 27.655 1.00 99.90 1916 CD1 ILE 761 21.527 60.456 26.954 1.00 99.90 1917 N PRO 762 24.805 61.698 31.308 1.00 27.54 1918 CA PRO 762 26.081 61.376 31.948 1.00 27.73 1919 C PRO 762 25.963 60.143 32.868 1.00 24.86 1920 O PRO 762 26.847 59.293 32.895 1.00 25.75 1921 CB PRO 762 26.399 62.656 32.715 1.00 27.68 1922 CG PRO 762 25.760 63.728 31.833 1.00 26.00 1923 CD PRO 762 24.403 63.078 31.631 1.00 28.16 1924 N LYS 763 24.872 60.049 33.620 1.00 23.19 1925 CA LYS 763 24.668 58.912 34.523 1.00 24.99 1926 C LYS 763 24.555 57.617 33.722 1.00 26.95 1927 O LYS 763 25.189 56.609 34.046 1.00 26.77 1928 CB LYS 763 23.391 59.124 35.346 1.00 31.71 1929 CG LYS 763 23.098 58.039 36.368 1.00 36.39 1930 CD LYS 763 21.730 58.277 37.013 1.00 41.59 1931 CE LYS 763 21.668 59.627 37.724 1.00 46.46 1932 NZ LYS 763 20.287 59.994 38.237 1.00 52.55 1933 N TYR 764 23.747 57.644 32.667 1.00 25.62 1934 CA TYR 764 23.577 56.459 31.820 1.00 25.44 1935 C TYR 764 24.904 56.027 31.211 1.00 28.84 1936 O TYR 764 25.260 54.850 31.252 1.00 23.14 1937 CB TYR 764 22.588 56.747 30.692 1.00 25.43 1938 CG TYR 764 21.157 57.110 31.106 1.00 99.90 1939 CD1 TYR 764 20.748 58.447 31.092 1.00 99.90 1940 CD2 TYR 764 20.258 56.118 31.507 1.00 99.90 1941 CE1 TYR 764 19.456 58.789 31.480 1.00 99.90 1942 CE2 TYR 764 18.965 56.463 31.896 1.00 99.90 1943 CZ TYR 764 18.566 57.796 31.882 1.00 99.90 1944 OH TYR 764 17.298 58.130 32.266 1.00 99.90 1945 N SER 765 25.633 56.971 30.624 1.00 26.45 1946 CA SER 765 26.936 56.647 30.027 1.00 29.61 1947 C SER 765 27.932 56.082 31.028 1.00 30.39 1948 O SER 765 28.733 55.198 30.698 1.00 32.46 1949 CB SER 765 27.545 57.887 29.360 1.00 27.19 1950 OG SER 765 27.957 58.882 30.304 1.00 99.90 1951 N ASN 766 27.897 56.594 32.249 1.00 28.14 1952 CA ASN 766 28.813 56.116 33.266 1.00 29.10 1953 C ASN 766 28.409 54.720 33.734 1.00 29.03 1954 O ASN 766 29.116 54.104 34.515 1.00 32.66 1955 CB ASN 766 28.845 57.089 34.433 1.00 25.78 1956 CG ASN 766 29.221 58.540 34.116 1.00 99.90 1957 OD1 ASN 766 28.382 59.422 34.006 1.00 99.90 1958 ND2 ASN 766 30.480 58.839 33.935 1.00 99.90 1959 N GLY 767 27.274 54.218 33.247 1.00 30.49 1960 CA GLY 767 26.826 52.893 33.652 1.00 30.14 1961 C GLY 767 26.212 52.842 35.048 1.00 28.27 1962 O GLY 767 26.277 51.815 35.724 1.00 35.23 1963 N ASN 768 25.613 53.942 35.492 1.00 27.77 1964 CA ASN 768 25.005 53.977 36.817 1.00 31.40 1965 C ASN 768 23.506 53.689 36.729 1.00 28.03 1966 O ASN 768 22.691 54.330 37.391 1.00 31.74 1967 CB ASN 768 25.266 55.335 37.472 1.00 32.66 1968 CG ASN 768 26.730 55.763 37.620 1.00 99.90 1969 OD1 ASN 768 27.260 56.553 36.853 1.00 99.90 1970 ND2 ASN 768 27.441 55.248 38.587 1.00 99.90 1971 N ILE 769 23.172 52.725 35.879 1.00 29.55 1972 CA ILE 769 21.802 52.273 35.653 1.00 28.30 1973 C ILE 769 21.875 50.778 35.406 1.00 31.38 1974 O ILE 769 22.944 50.244 35.111 1.00 28.00 1975 CB ILE 769 21.151 52.942 34.422 1.00 27.98 1976 CG2 ILE 769 19.658 52.531 34.229 1.00 99.90 1977 CG1 ILE 769 21.229 54.503 34.411 1.00 99.90 1978 CD1 ILE 769 20.887 55.185 33.070 1.00 99.90 1979 N LYS 770 20.731 50.112 35.511 1.00 28.65 1980 CA LYS 770 20.657 48.673 35.344 1.00 27.13 1981 C LYS 770 19.961 48.263 34.051 1.00 27.33 1982 O LYS 770 18.737 48.229 33.971 1.00 26.71 1983 CB LYS 770 19.922 48.079 36.543 1.00 30.31 1984 CG LYS 770 19.641 46.598 36.440 1.00 36.48 1985 CD LYS 770 18.845 46.130 37.649 1.00 42.65 1986 CE LYS 770 18.386 44.692 37.468 1.00 45.66 1987 NZ LYS 770 19.510 43.707 37.195 1.00 41.46 1988 N LYS 771 20.743 47.945 33.013 1.00 29.35 1989 CA LYS 771 20.153 47.543 31.738 1.00 29.76 1990 C LYS 771 19.501 46.177 31.940 1.00 32.65 1991 O LYS 771 20.108 45.300 32.554 1.00 31.57 1992 CB LYS 771 21.372 47.462 30.817 1.00 32.15 1993 CG LYS 771 21.013 47.119 29.349 1.00 99.90 1994 CD LYS 771 22.214 46.965 28.412 1.00 99.90 1995 CE LYS 771 21.719 46.557 27.018 1.00 99.90 1996 NZ LYS 771 22.849 46.576 26.072 1.00 99.90 1997 N LEU 772 18.269 45.986 31.471 1.00 26.08 1998 CA LEU 772 17.643 44.678 31.634 1.00 28.80 1999 C LEU 772 17.957 43.890 30.386 1.00 32.70 2000 O LEU 772 17.814 44.396 29.272 1.00 32.54 2001 CB LEU 772 16.125 44.804 31.825 1.00 28.21 2002 CG LEU 772 15.741 45.638 33.053 1.00 27.44 2003 CD1 LEU 772 14.223 45.661 33.216 1.00 25.95 2004 CD2 LEU 772 16.400 45.046 34.305 1.00 28.60 2005 N LEU 773 18.403 42.656 30.572 1.00 29.11 2006 CA LEU 773 18.768 41.800 29.447 1.00 32.04 2007 C LEU 773 17.933 40.528 29.413 1.00 33.98 2008 O LEU 773 17.604 39.979 30.462 1.00 35.14 2009 CB LEU 773 20.253 41.426 29.552 1.00 30.80 2010 CG LEU 773 21.245 42.595 29.527 1.00 41.73 2011 CD1 LEU 773 22.654 42.099 29.847 1.00 37.07 2012 CD2 LEU 773 21.198 43.263 28.165 1.00 38.20 2013 N PHE 774 17.580 40.075 28.211 1.00 30.93 2014 CA PHE 774 16.815 38.838 28.065 1.00 36.94 2015 C PHE 774 17.728 37.626 28.056 1.00 37.82 2016 O PHE 774 17.306 36.518 28.390 1.00 40.73 2017 CB PHE 774 16.011 38.820 26.771 1.00 33.98 2018 CG PHE 774 14.787 39.666 26.818 1.00 31.86 2019 CD1 PHE 774 13.620 39.164 27.384 1.00 27.98 2020 CD2 PHE 774 14.803 40.967 26.346 1.00 29.84 2021 CE1 PHE 774 12.488 39.955 27.478 1.00 34.01 2022 CE2 PHE 774 13.668 41.769 26.435 1.00 31.12 2023 CZ PHE 774 12.514 41.264 27.002 1.00 31.58 2024 N HIS 775 18.975 37.839 27.659 1.00 39.64 2025 CA HIS 775 19.937 36.755 27.605 1.00 43.59 2026 C HIS 775 21.178 37.074 28.410 1.00 45.74 2027 O HIS 775 21.780 38.133 28.258 1.00 48.72 2028 CB HIS 775 20.286 36.470 26.149 1.00 41.38 2029 CG HIS 775 19.079 36.205 25.308 1.00 44.29 2030 ND1 HIS 775 18.211 35.169 25.572 1.00 49.69 2031 CD2 HIS 775 18.541 36.892 24.274 1.00 48.24 2032 CE1 HIS 775 17.187 35.231 24.738 1.00 50.45 2033 NE2 HIS 775 17.364 36.268 23.940 1.00 49.57 2034 N GLN 776 21.531 36.142 29.288 1.00 50.39 2035 CA GLN 776 22.698 36.254 30.150 1.00 56.63 2036 C GLN 776 23.960 36.339 29.302 1.00 53.01 2037 O GLN 776 23.958 35.647 28.265 1.00 56.94 2038 CB GLN 776 22.748 35.026 31.061 1.00 57.98 2039 CG GLN 776 22.461 33.738 30.299 1.00 61.12 2040 CD GLN 776 22.409 32.412 31.067 1.00 99.90 2041 OE1 GLN 776 22.143 31.364 30.499 1.00 99.90 2042 NE2 GLN 776 22.627 32.394 32.357 1.00 99.90 2043 CB GLU 685 16.805 65.125 37.380 1.00 63.65 2044 CG GLU 685 16.240 65.106 38.791 1.00 63.87 2045 CD GLU 685 15.337 63.914 39.036 1.00 64.23 2046 OE1 GLU 685 14.222 63.893 38.474 1.00 64.28 2047 OE2 GLU 685 15.741 62.998 39.783 1.00 64.53 2048 C GLU 685 16.202 67.392 36.510 1.00 61.94 2049 O GLU 685 16.230 67.976 35.426 1.00 62.27 2050 N GLU 685 18.175 67.207 37.988 1.00 62.90 2051 CA GLU 685 17.353 66.483 36.931 1.00 62.73 2052 N ARG 686 15.189 67.501 37.368 1.00 60.58 2053 CA ARG 686 14.026 68.343 37.098 1.00 59.13 2054 CB ARG 686 14.484 69.737 36.657 1.00 60.07 2055 CG ARG 686 13.371 70.752 36.441 1.00 61.27 2056 CD ARG 686 12.980 71.452 37.735 1.00 62.16 2057 NE ARG 686 12.286 72.710 37.474 1.00 63.43 2058 CZ ARG 686 11.075 72.803 36.934 1.00 64.44 2059 NH1 ARG 686 10.244 71.724 36.777 1.00 64.89 2060 NH2 ARG 686 10.622 74.033 36.555 1.00 65.34 2061 C ARG 686 13.106 67.744 36.030 1.00 57.39 2062 O ARG 686 12.108 67.097 36.352 1.00 58.48 2063 N HIS 687 13.452 67.962 34.764 1.00 54.71 2064 CA HIS 687 12.666 67.470 33.632 1.00 51.16 2065 CB HIS 687 12.415 65.962 33.752 1.00 51.72 2066 CG HIS 687 13.660 65.132 33.685 1.00 51.47 2067 CD2 HIS 687 14.122 64.297 32.725 1.00 51.61 2068 ND1 HIS 687 14.601 65.118 34.691 1.00 52.04 2069 CE1 HIS 687 15.590 64.308 34.354 1.00 51.83 2070 NE2 HIS 687 15.324 63.798 33.166 1.00 51.34 2071 C HIS 687 11.333 68.204 33.547 1.00 48.80 2072 O HIS 687 10.272 67.584 33.498 1.00 48.44 2073 N ALA 688 11.400 69.531 33.519 1.00 45.79 2074 CA ALA 688 10.208 70.370 33.454 1.00 43.75 2075 CB ALA 688 10.613 71.841 33.459 1.00 43.70 2076 C ALA 688 9.318 70.085 32.246 1.00 41.94 2077 O ALA 688 8.143 69.755 32.400 1.00 40.94 2078 N ILE 689 9.879 70.215 31.048 1.00 40.75 2079 CA ILE 689 9.121 69.990 29.823 1.00 39.42 2080 CB ILE 689 10.010 70.192 28.579 1.00 39.12 2081 CG2 ILE 689 9.240 69.818 27.316 1.00 38.63 2082 CG1 ILE 689 10.466 71.652 28.513 1.00 38.90 2083 CD1 ILE 689 11.342 71.978 27.322 1.00 39.20 2084 C ILE 689 8.483 68.606 29.772 1.00 38.83 2085 O ILE 689 7.292 68.474 29.487 1.00 37.60 2086 N LEU 690 9.276 67.579 30.053 1.00 38.40 2087 CA LEU 690 8.774 66.213 30.040 1.00 38.63 2088 CB LEU 690 9.893 65.247 30.435 1.00 39.36 2089 CG LEU 690 9.858 63.847 29.820 1.00 40.30 2090 CD1 LEU 690 11.172 63.130 30.105 1.00 39.81 2091 CD2 LEU 690 8.682 63.064 30.374 1.00 41.50 2092 C LEU 690 7.602 66.111 31.017 1.00 39.78 2093 O LEU 690 6.543 65.578 30.679 1.00 38.83 2094 N HIS 691 7.789 66.633 32.227 1.00 40.27 2095 CA HIS 691 6.726 66.614 33.229 1.00 41.72 2096 CB HIS 691 7.181 67.316 34.509 1.00 43.49 2097 CG HIS 691 7.873 66.413 35.480 1.00 45.34 2098 CD2 HIS 691 9.155 66.387 35.917 1.00 46.24 2099 ND1 HIS 691 7.226 65.386 36.131 1.00 46.60 2100 CE1 HIS 691 8.079 64.767 36.928 1.00 46.83 2101 NE2 HIS 691 9.256 65.355 36.817 1.00 47.22 2102 C HIS 691 5.487 67.312 32.681 1.00 41.36 2103 O HIS 691 4.372 66.800 32.795 1.00 41.77 2104 N ARG 692 5.692 68.482 32.085 1.00 40.51 2105 CA ARG 692 4.592 69.250 31.511 1.00 40.58 2106 CB ARG 692 5.131 70.500 30.815 1.00 41.97 2107 CG ARG 692 4.061 71.442 30.275 1.00 44.31 2108 CD ARG 692 4.690 72.501 29.383 1.00 46.39 2109 NE ARG 692 5.286 71.900 28.191 1.00 48.87 2110 CZ ARG 692 6.094 72.537 27.349 1.00 49.52 2111 NH1 ARG 692 6.586 73.791 27.593 1.00 50.67 2112 NH2 ARG 692 6.422 71.914 26.185 1.00 49.63 2113 C ARG 692 3.823 68.392 30.508 1.00 39.77 2114 O ARG 692 2.612 68.204 30.642 1.00 38.70 2115 N LEU 693 4.532 67.870 29.509 1.00 38.99 2116 CA LEU 693 3.917 67.031 28.482 1.00 39.44 2117 CB LEU 693 4.984 66.418 27.567 1.00 38.36 2118 CG LEU 693 5.747 67.337 26.608 1.00 38.71 2119 CD1 LEU 693 6.769 66.517 25.841 1.00 37.17 2120 CD2 LEU 693 4.781 68.014 25.646 1.00 37.74 2121 C LEU 693 3.082 65.913 29.088 1.00 40.12 2122 O LEU 693 1.998 65.599 28.598 1.00 40.20 2123 N LEU 694 3.591 65.310 30.155 1.00 41.30 2124 CA LEU 694 2.880 64.224 30.814 1.00 43.03 2125 CB LEU 694 3.814 63.511 31.793 1.00 41.27 2126 CG LEU 694 4.944 62.707 31.142 1.00 40.09 2127 CD1 LEU 694 5.933 62.249 32.194 1.00 39.04 2128 CD2 LEU 694 4.351 61.515 30.400 1.00 39.24 2129 C LEU 694 1.634 64.710 31.547 1.00 45.64 2130 O LEU 694 0.736 63.920 31.838 1.00 44.78 2131 N GLN 695 1.575 66.007 31.832 1.00 49.29 2132 CA GLN 695 0.436 66.580 32.546 1.00 53.51 2133 CB GLN 695 0.780 67.978 33.075 1.00 53.94 2134 CG GLN 695 2.068 68.066 33.890 1.00 54.96 2135 CD GLN 695 2.065 67.191 35.133 1.00 55.61 2136 OE1 GLN 695 3.023 67.202 35.911 1.00 55.52 2137 NE2 GLN 695 0.874 66.592 35.592 1.00 55.62 2138 C GLN 695 −0.834 66.666 31.699 1.00 55.94 2139 O GLN 695 −1.931 66.813 32.236 1.00 55.76 2140 N GLU 696 −0.686 66.579 30.380 1.00 58.97 2141 CA GLU 696 −1.829 66.652 29.470 1.00 62.61 2142 CB GLU 696 −2.620 67.945 29.711 1.00 63.02 2143 CG GLU 696 −1.785 69.190 30.082 1.00 63.82 2144 CD GLU 696 −0.758 69.598 29.037 1.00 64.13 2145 OE1 GLU 696 −1.131 69.774 27.856 1.00 64.51 2146 OE2 GLU 696 0.422 69.758 29.402 1.00 64.16 2147 C GLU 696 −1.374 66.630 28.019 1.00 64.98 2148 O GLU 696 −2.107 66.233 27.112 1.00 65.58 2149 N GLY 697 −0.140 67.073 27.836 1.00 67.35 2150 CA GLY 697 0.479 67.171 26.535 1.00 70.03 2151 C GLY 697 1.252 68.446 26.701 1.00 71.80 2152 O GLY 697 1.323 69.262 25.756 1.00 71.76 2153 OXT GLY 697 1.783 68.647 27.817 1.00 71.76

It will be understood that various details of the invention may be changed without departing from the scope of the invention. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation—the invention being defined by the claims. 

1. A method of modifying a test NR polypeptide, the method comprising: (a) providing a test NR polypeptide sequence having a characteristic that is targeted for modification; (b) aligning the test NR polypeptide sequence with at least one reference NR polypeptide sequence for which an X-ray structure is available, wherein the at least one reference NR polypeptide sequence has a characteristic that is desired for the test NR polypeptide; (c) building a three-dimensional model for the test NR polypeptide using the three-dimensional coordinates of the X-ray structure(s) of the at least one reference polypeptide and its sequence alignment with the test NR polypeptide sequence; (d) examining the three-dimensional model of the test NR polypeptide for a difference in an amino acid residue as compared to the at least one reference polypeptide, wherein the residues are associated with the desired characteristic; and (c) mutating an amino acid residue in the test NR polypeptide sequence located at a difference identified in step (d) to a residue associated with the desired characteristic, whereby the test NR polypeptide is modified.
 2. The method of claim 1, wherein the reference NR polypeptide sequence is a PR sequence, and wherein the test polypeptide sequence is a GR polypeptide sequence.
 3. The method of claim 1, wherein the polypeptide of a crystalline GR LBD is used as the reference polypeptide sequence.
 4. The method of claim 1, wherein the method is carried out in a bacterial expression system.
 5. The method of claim 1, wherein the bacteria is E. coli.
 6. A method for modifying a test NR polypeptide to improve the solubility, stability in solution and other solution behavior, to alter and preferably improve the folding and stability of the folded structure, to alter and preferably improve the ability to form ordered crystals, or combination thereof, the method comprising: (a) providing a test NR polypeptide sequence for which the solubility, stability in solution, other solution behavior, tendency to fold properly, ability to form ordered crystals, or combination thereof is different from that desired; (b) aligning the test NR polypeptide sequence with the sequences of one or more reference NR polypeptides for which the X-ray structure is available and for which the solution properties, folding behavior and crystallization properties are closer to those desired; (c) building a three-dimensional model for the test NR polypeptide using the three-dimensional coordinates of the X-ray structure(s) of the one or more of reference polypeptides and their sequence alignment with the test NR polypetide sequence; (d) examining the three-dimensional model of the test NR polypeptide for lipophilic side-chains that are exposed to solvent, for clusters of two or more lipophilic side-chains exposed to solvent, for lipophilic pockets and clefts on the surface of the protein model, for sites on the surface of the protein model that are more lipophilic than the corresponding sites on the structure(s) of the reference NR polypeptide(s), or combinations thereof; (e) for each residue identified in step (d), mutating the amino acid to an amino acid with different hydrophilicity, whereby the exposed lipophilic sites are reduced, and the solution properties improved; (f) examining the three-dimensional model at each site where the amino acid in the test NR polypeptide is different from the amino acid at the corresponding position in the reference NR polypeptide, and checking whether the amino acid in the test NR polypeptide makes favorable interactions with the atoms that lie around it in the three-dimensional model, considering the side-chain conformations predicted in step (c), considering alternative conformations of the side-chains, considering the presence of water molecules, or combinations thereof; (g) for each residue identified in step (f) as not making favorable interactions with the atoms that lie around it, mutating the residue to another amino acid that makes favorable interactions with the atoms that lie around it, thereby promoting the tendency for the test NR polypeptide to fold into a stable structure with improved solution properties, less tendency to unfold, and greater tendency to form ordered crystals; (h) examining the three-dimensional model at each residue position where the amino acid in the test NR polypeptide is different from the amino acid at the corresponding position in the reference NR polypeptide, and checking whether the steric packing, hydrogen bonding and other energetic interactions could be improved by mutating that residue or any one or more of the surrounding residues lying within 8 angstroms in the three-dimensional model; (i) for each residue position identified in step (h) as potentially allowing an improvement in the packing, hydrogen bonding and energetic interactions, mutating those residues individually or in combination to residues that improve the packing, hydrogen bonding, energetic interactions, and combinations thereof, thereby promoting the tendency for the test NR polypeptide to fold into a stable structure with improved solution properties, less tendency to unfold, and greater tendency to form ordered crystals.
 7. The method of claim 6, further comprising optimizing the side-chain conformations in the three-dimensional model of the test NR polypeptide by generating many alternative side-chain conformations, refining by energy minimization, and selecting side-chain conformations with lower energy.
 8. The method of claim 6, wherein the mutating of step (e) further comprises a mutation to a more hydrophilic amino acid.
 9. The method of claim 6, wherein the reference NR polypeptide is PR, and wherein the test NR polypeptide is GRα.
 10. The method of claim 6, wherein the reference NR polypeptide is GRα, and wherein the test NR polypeptide is GRβ or MR.
 11. The method of claim 6, wherein the method is carried out in a bacterial expression system.
 12. The method of claim 6, wherein the bacteria is E. coli.
 13. An isolated GR polypeptide comprising a mutation in a ligand binding domain, wherein the mutation alters the solubility of the ligand binding domain.
 14. An isolated GR polypeptide, or functional portion thereof, having one or more mutations comprising a substitution of a hydrophobic amino acid residue by a hydrophilic amino acid residue in a ligand binding domain.
 15. The isolated polypeptide of claim 13, wherein the mutation is at a residue selected from the group consisting of V552, W557, F602, L636, Y648, W712, L741, L535, V538, C638, M691, V702, Y648, Y660, L685, M691, V702, W712, L733, Y764 and combinations thereof.
 16. The isolated polypeptide of claim 13, wherein the mutation is selected from the group consisting of V552K, W557S, F602S, F602D, F602E, F602Y, F602T, F602N, F602C., L636E, Y648Q, W712S, L741R, L535T, V538S, C638S, M691T, V702T, W712T and combinations thereof.
 17. An isolated GR LBD polypeptide, or functional portion thereof, having a F602S mutation or a F602D mutation, or a phenylalanine to serine or phenylalanine to aspartic acid mutation at an analogous position in the sequence in any polypeptide based on sequence alignment to GRα.
 18. The isolated polypeptide of claim 17, wherein the polypeptide has the sequence of SEQ ID NO:12 or
 14. 19. An isolated nucleic acid molecule encoding a GR polypeptide of claim
 13. 20. A chimeric gene, comprising the nucleic acid molecule of claim 19 operably linked to a heterologous promoter.
 21. A vector comprising the chimeric gene of claim
 20. 22. A host cell comprising the chimeric gene of claim
 20. 23. A method of detecting a nucleic acid molecule that encodes a GR polypeptide, the method comprising: (a) procuring a biological sample comprising nucleic acid material; (b) hybridizing the nucleic acid molecule of claim 19 under stringent hybridization conditions to the biological sample of (a), thereby forming a duplex structure between the nucleic acid of claim 19 and a nucleic acid within the biological sample; and (c) detecting the duplex structure of (b), whereby a GR encoding nucleic acid molecule is detected.
 24. An antibody that specifically recognizes a GR polypeptide of claim
 13. 25. A method for producing an antibody that specifically recognizes a GR polypeptide, the method comprising: (a) recombinantly or synthetically producing a GR polypeptide of claim 13, or portion thereof; (b) formulating the polypeptide of (a) whereby it is an effective immunogen; (c) administering to an animal the formulation of (b) to generate an immune response in the animal comprising production of antibodies, wherein antibodies are present in the blood serum of the animal; and (d) collecting the blood serum from the animal of (c), the blood serum comprising antibodies that specifically recognize a GR polypeptide.
 26. A method for detecting a level of GR polypeptide, the method comprising: (a) obtaining a biological sample comprising peptidic material; and (b) detecting a GR polypeptide in the biological sample of (a) by immunochemical reaction with the antibody of claim 24, whereby an amount of GR polypeptide in a sample is determined.
 27. A method for identifying a substance that modulates GR LBD function, the method comprising: (a) isolating a GR LBD polypeptide of claim 13; (b) exposing the isolated GR polypeptide to a plurality of substances; (c) assaying binding of a substance to the isolated GR polypeptide; and (d) selecting a substance that demonstrates specific binding to the isolated GR LBD polypeptide.
 28. A substantially pure GR ligand binding domain polypeptide in crystalline form.
 29. The polypeptide of claim 28, wherein the crystalline form comprises lattice constants of a=b=126.014 Å, c=86.312 Å, a=90°, β=90°, γ=120°.
 30. The polypeptide of claim 28, wherein the crystalline form is a hexagonal crystalline form.
 31. The polypeptide of claim 28, wherein the crystalline form has a space group of P6₁.
 32. The polypeptide of claim 28, wherein the GRα ligand binding domain polypeptide has the amino acid sequence shown in any one of SEQ ID NOs:12, 14, 16 and
 31. 33. The polypeptide of claim 28, wherein the GR ligand binding domain polypeptide is in complex with a ligand.
 34. The polypeptide of claim 33, wherein the ligand is a steroid.
 35. The polypeptide of claim 34, wherein the steroid is dexamethasone.
 36. The polypeptide of claim 28, wherein the GR ligand binding domain polypeptide is in complex with a ligand and a peptide.
 37. The polypeptide of claim 36, wherein the ligand is a steroid.
 38. The polypeptide of claim 37, wherein the steroid is dexamethasone.
 39. The polypeptide of claim 38, wherein the ligand is a steroid and the peptide is a fragment of a co-activator.
 40. The polypeptide of claim 36, wherein the ligand is a steroid and the peptide is a fragment of a co-repressor.
 41. The polypeptide of claim 36, wherein the ligand is dexamethasone and the peptide comprises an LXXLL (SEQ ID NO:18) motif.
 42. The polypeptide of claim 36, wherein the peptide is a fragment of a TIF2 protein.
 43. The polypeptide of claim 42, wherein the ligand is dexamethasone and the peptide has the amino acid sequence shown in any one of SEQ ID NO:17.
 44. The polypeptide of claim 28, wherein the GR ligand binding domain has a crystalline structure further characterized by the atomic structure coordinates shown in Table
 4. 45. The polypeptide of claim 28, wherein the crystalline form contains two GRα ligand binding domain polypeptide in the asymmetric unit.
 46. The polypeptide of claim 28, wherein the crystalline form is such that the three-dimensional structure of the crystallized GR ligand binding domain polypeptide can be determined to a resolution of about 2.8 Å or better.
 47. The polypeptide of claim 28, wherein the crystalline form contains one or more atoms having a molecular weight of 40 grams/mol or greater.
 48. A method for determining the three-dimensional structure of a crystallized GR ligand binding domain polypeptide to a resolution of about 2.8 Å or better, the method comprising: (a) crystallizing a GR ligand binding domain polypeptide; and (b) analyzing the GR ligand binding domain polypeptide to determine the three-dimensional structure of the crystallized GR ligand binding domain polypeptide, whereby the three-dimensional structure of a crystallized GR ligand binding domain polypeptide is determined to a resolution of about 2.8 Å or better.
 49. The method of claim 48, wherein the analyzing is by X-ray diffraction.
 50. The method of claim 48, wherein the crystallization is accomplished by the hanging drop method, and wherein the GR ligand binding domain is mixed with a reservoir.
 51. The method of claim 50, wherein the reservoir comprises 50mM HEPES, pH 7.5-8.5, and 1.7-2.3M ammonium formate.
 52. The method of claim 48, wherein the crystallizing further comprises crystallizing the GRα ligand binding domain with a ligand and a peptide.
 53. The method of claim 52, wherein the ligand is a steroid.
 54. The method of claim 53, wherein the ligand is dexamethasone.
 55. The method of claim 52, wherein the ligand is a steroid and the peptide is a fragment of a co-activator.
 56. The method of claim 52, wherein the ligand is a steroid and the peptide is a fragment of a co-repressor.
 57. The method of claim 52, wherein the ligand is dexamethasone and the peptide comprises an LXXLL (SEQ ID NO:18) motif.
 58. The method of claim 52, wherein the peptide is a fragment of a TIF2 protein.
 59. The method of claim 52, wherein the ligand is dexamethasone and the peptide has the amino acid sequence shown in SEQ ID NO:17.
 60. A method of generating a crystallized GR ligand binding domain polypeptide, the method comprising: (a) incubating a solution comprising a GR ligand binding domain with a reservoir; and (b) crystallizing the GR ligand binding domain polypeptide using the hanging drop method, whereby a crystallized GR ligand binding domain polypeptide is generated.
 61. The method of claim 60, wherein the incubating further comprises incubating the GR ligand binding domain with a ligand and a peptide.
 62. The method of claim 61, wherein the ligand is a steroid.
 63. The method of claim 62, wherein the steroid is dexamethasone.
 64. The method of claim 61, wherein the ligand is a steroid and the peptide is a fragment of a co-activator.
 65. The method of claim 61, wherein the ligand is a steroid and the peptide is a fragment of a co-repressor.
 66. The method of claim 61, wherein the ligand is dexamethasone and the peptide comprises an LXXLL (SEQ ID NO:18) motif.
 67. The method of claim 61, wherein the peptide is a fragment of a TIF2 protein.
 68. A crystallized GRα ligand binding domain polypeptide produced by the method of claim
 60. 69. A method of designing a modulator of a nuclear receptor, the method comprising: (a) designing a potential modulator of a nuclear receptor that will make interactions with amino acids in the ligand binding site of the nuclear receptor based upon the atomic structure coordinates of a GR ligand binding domain polypeptide; (b) synthesizing the modulator; and (c) determining whether the potential modulator modulates the activity of the nuclear receptor, whereby a modulator of a nuclear receptor is designed.
 70. The method of claim 69, wherein the atomic structure coordinates further comprises a ligand and a peptide bound to the GR ligand binding domain polypeptide.
 71. The method of claim 69, wherein the atomic structure coordinates are the atomic structural coordinates shown in Table
 3. 72. The method of claim 70, wherein the ligand is a steroid.
 73. The method of claim 72, wherein the steroid is dexamethasone.
 74. The method of claim 70, wherein the ligand is a steroid and the peptide is a fragment of a co-activator.
 75. The method of claim 70, wherein the ligand is a steroid and the peptide is a fragment of a co-repressor.
 76. The method of claim 70, wherein the ligand is dexamethasone and the peptide comprises an LXXLL (SEQ ID NO:18) motif.
 77. The method of claim 70, wherein the peptide is a fragment of a TIF2 protein.
 78. A method of designing a modulator that selectively modulates the activity of a GRα polypeptide the method comprising: (a) obtaining a crystalline form of a GRα ligand binding domain polypeptide; (b) determining the three-dimensional structure of the crystalline form of the GRα ligand binding domain polypeptide; and (c) synthesizing a modulator based on the three-dimensional structure of the crystalline form of the GRα ligand binding domain polypeptide, whereby a modulator that selectively modulates the activity of a GRα polypeptide is designed.
 79. The method of claim 78, wherein the method further comprises contacting a GRα ligand binding domain polypeptide with the potential modulator; and assaying the GRα ligand binding domain polypeptide for binding of the potential modulator, for a change in activity of the GRα ligand binding domain polypeptide, or both.
 80. The method of claim 78, wherein the crystalline form is a hexagonal form.
 81. The method of claim 80, wherein the crystals are such that the three-dimensional structure of the crystallized GRα ligand binding domain polypeptide can be determined to a resolution of about 2.8 Å or better.
 82. The method of claim 78, wherein the crystalline form comprises a GR□ ligand binding domain with a ligand and a peptide.
 83. The method of claim 82, wherein the ligand is a steroid.
 84. The method of claim 83, wherein the steroid is dexamethasone.
 85. The method of claim 82, wherein the ligand is a steroid and the peptide is a fragment of a co-activator.
 86. The method of claim 82, wherein the ligand is a steroid and the peptide is a fragment of a co-repressor.
 87. The method of claim 82, wherein the ligand is dexamethasone and the peptide comprises an LXXLL (SEQ ID NO:18) motif.
 88. The method of claim 82, wherein the peptide is a fragment of a TIF2 protein.
 89. The method of claim 78, wherein the three-dimensional structure of the crystalline form of the GRα ligand binding domain polypeptide is described by the atomic coordinates shown in Table
 4. 90. A method of screening a plurality of compounds for a modulator of a GR ligand binding domain polypeptide, the method comprising: (a) providing a library of test samples; (b) contacting a GR ligand binding domain polypeptide with each test sample; (c) detecting an interaction between a test sample and the GR ligand binding domain polypeptide; (d) identifying a test sample that interacts with the GR ligand binding domain polypeptide; and (e) isolating a test sample that interacts with the GR ligand binding domain polypeptide, whereby a plurality of compounds is screened for a modulator of a GR ligand binding domain polypeptide.
 91. The method of claim 90, wherein the test samples are bound to a substrate.
 92. The method of claim 90, wherein the test samples are synthesized directly on a substrate.
 93. A method for identifying a GR modulator, the method comprising: (a) providing atomic coordinates of a GR ligand binding domain to a computerized modeling system; and (b) modeling ligands that fit spatially into the binding pocket of the GR ligand binding domain to thereby identify a GR modulator, whereby a GR modulator is identified.
 94. The method of claim 93, wherein the method further comprises identifying in an assay for GR-mediated activity a modeled ligand that increases or decreases the activity of the GR.
 95. The method of claim 93, wherein the atomic coordinates are the atomic coordinates shown in Table
 4. 96. A method of identifying modulator that selectively modulates the activity of a GRα polypeptide compared to other GR polypeptides, the method comprising: (a) providing atomic coordinates of a GRα ligand binding domain to a computerized modeling system; and (b) modeling a ligand that fits into the binding pocket of a GRα ligand binding domain and that interacts with conformationally constrained residues of a GRα conserved among GR subtypes, whereby a modulator that selectively modulates the activity of a GRα polypeptide compared to other polypeptides is identified.
 97. The method of claim 96, wherein the method further comprises identifying in a biological assay for GR activity a modeled ligand that selectively binds to GRα and increases or decreases the activity of said GRα.
 98. The method of claim 96, wherein the atomic coordinates are the atomic coordinates shown in Table
 4. 99. A method of designing a modulator of a GR polypeptide, the method comprising: (a) selecting a candidate GR ligand; (b) determining which amino acid or amino acids of a GR polypeptide interact with the ligand using a three-dimensional model of a crystallized protein comprising a GRα LBD; (c) identifying in a biological assay for GR activity a degree to which the ligand modulates the activity of the GR polypeptide; (d) selecting a chemical modification of the ligand wherein the interaction between the amino acids of the GR polypeptide and the ligand is predicted to be modulated by the chemical modification; (e) synthesizing a chemical compound with the selected chemical modification to form a modified ligand; (f) contacting the modified ligand with the GR polypeptide; (g) identifying in a biological assay for GR activity a degree to which the modified ligand modulates the biological activity of the GR polypeptide; and (h) comparing the biological activity of the GR polypeptide in the presence of modified ligand with the biological activity of the GR polypeptide in the presence of the unmodified ligand, whereby a modulator of a GR polypeptide is designed.
 100. The method of claim 99, wherein the GR polypeptide is a GRα polypeptide.
 101. The method of claim 99, wherein the three-dimensional model of a crystallized protein is a GRα ligand binding domain with a ligand and a peptide.
 102. The method of claim 101, wherein the ligand is a steroid.
 103. The method of claim 101, wherein the steroid is dexamethasone.
 104. The method of claim 101, wherein the ligand is a steroid and the peptide is a fragment of a co-activator.
 105. The method of claim 101, wherein the ligand is a steroid and the peptide is a fragment of a co-repressor.
 106. The method of claim 101, wherein the ligand is dexamethasone and the peptide comprises an LXXLL (SEQ ID NO:18) motif.
 107. The method of claim 101, wherein the peptide is a fragment of a TIF2 protein.
 108. The method of claim 99, wherein the three-dimensional model is represented by the three dimensional coordinates shown in Table
 4. 109. The method of claim 99, wherein the method further comprises repeating steps (a) through (f), if the biological activity of the GR polypeptide in the presence of the modified ligand varies from the biological activity of the GR polypeptide in the presence of the unmodified ligand.
 110. An assay method for identifying a compound that inhibits binding of a ligand to a GR polypeptide, the assay method comprising: (a) designing a test inhibitor compound based on the three dimensional atomic coordinates of GR; (b) incubating a GR polypeptide with a ligand in the presence of a test inhibitor compound; (c) determining an amount of ligand that is bound to the GR polypeptide, wherein decreased binding of ligand to the GR protein in the presence of the test inhibitor compound relative to binding of ligand in the absence of the test inhibitor compound is indicative of inhibition; and (d) identifying the test compound as an inhibitor of ligand binding if decreased ligand binding is observed, whereby a compound that inhibits binding of a ligand to a GR polypeptide is identified.
 111. The method of claim 110, wherein the ligand is a steroid.
 112. The method of claim 111, wherein the steroid is dexamethasone.
 113. The method of claim 110, wherein the three dimensional coordinates are the three dimensional coordinates shown in Table
 4. 114. A method of identifying a NR modulator that selectively modulates the biological activity of one NR compared to GRα, the method comprising: (a) providing an atomic structure coordinate set describing a GRα ligand binding domain structure and at least one other atomic structure coordinate set describing a NR ligand binding domain, each ligand binding domain comprising a ligand binding site; (b) comparing the atomic structure coordinate sets to identify at least one diference between the sets; (c) designing a candidate ligand predicted to interact with the difference of step (b); (d) synthesizing the candidate ligand; and (e) testing the synthesized candidate ligand for an ability to selectively modulate a NR as compared to GRα, whereby a NR modulator that selectively modulates the biological activity NR compared to GRα is identified.
 115. The method of claim 114, wherein the GRα atomic structure coordinate set is the atomic structure coordinate set shown in Table
 4. 116. The method of claim 114, wherein the NR is selected from the group consisting of MR, PR, AR, GRβ and isoforms thereof that have ligands that also bind GRα. 